Total submissions: 51
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000007223 | SCV000616382 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2017-04-03 | reviewed by expert panel | curation | The c.4A>G (p.Ser2Gly) variant in SHOC2 has been reported as a confirmed de novo occurrence in multiple patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; ClinVar SCV000062456.5, SCV000209051.10, SCV000263045.1 PMID 19684605, 21548061, 23918763, 22528146). The p.Ser2Gly variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data GTR ID's: 506381, 28338; PMID: 25563136, 24458587). In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SHOC2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS3, PS4, PM2, PP2. |
| Dasa | RCV000213000 | SCV007598944 | pathogenic | not provided | 2024-05-15 | criteria provided, single submitter | clinical testing | NM_007373.4(SHOC2):c.4A>G (p.Ser2Gly) is a missense variant that results in the substitution of serine with glycine. Functional evidence supports a deleterious effect on the gene or gene product (PMID: 19684605; PMID: 31059601; PMID: 21784453; PMID: 21548061; PMID: 22419608). This variant has been recurrently observed in individuals with related phenotype (PMID: 19684605; PMID: 31059601; PMID: 21784453; PMID: 21548061; PMID: 22419608). The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic. |
| Department of Human Genetics, |
RCV000007223 | SCV007540585 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2024-01-16 | criteria provided, single submitter | clinical testing | |
| Variantyx, |
RCV000007223 | SCV007448676 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2025-03-20 | criteria provided, single submitter | clinical testing | This is a nonsynonymous variant in the SHOC2 gene (OMIM: 602775). Pathogenic variants in this gene have been associated with autosomal dominant Noonan syndrome-like with loose anagen hair 1. This variant likely occurred de novo in the current proband proband and multiple individuals from the publisher literature; however, the possibility of parental germline mosaicism cannot be excluded (PMID: 19684605) (PS2_Very_Strong). This variant has a 0.0006% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/) (PM2_Supporting). Other reputable laboratories have reported this variant as pathogenic or likely pathogenic, and this classification has been validated by an expert panel in ClinVar (PP5). Computational algorithms produce conflicting evidence regarding the predicted functional impact of this variant (REVEL score: 0.39). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant Noonan syndrome-like with loose anagen hair 1. |
| Daryl Scott Lab, |
RCV006261934 | SCV007114105 | pathogenic | Houge-Janssens syndrome 2 | 2025-08-25 | criteria provided, single submitter | clinical testing | PS2, PS3, PS4, PM2, PP2 |
| Revvity Omics, |
RCV000007223 | SCV006321825 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2024-09-09 | criteria provided, single submitter | clinical testing | |
| Daryl Scott Lab, |
RCV000007223 | SCV005871372 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2024-01-01 | criteria provided, single submitter | clinical testing | PS2_VeryStrong, PS3, PS4, PM2, PP2 |
| Clinical Genomics Laboratory, |
RCV000007223 | SCV005685488 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2024-07-02 | criteria provided, single submitter | clinical testing | The SHOC2 c.4A>G (p.Ser2Gly) variant has been reported in multiple individuals with clinical features of a RASopathy and is reported as occurring de novo in at least three individuals (Choi JH et al., PMID: 25563136; Cordeddu V et al., PMID: 19684605; Ekvall S et al., PMID: 21548061; Gargano G et al., PMID: 24458587; Gripp KW et al., PMID: 23918763). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by 40 submitters including a classification of pathogenic by the ClinGen RASopathy Expert Panel. In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (Cordeddu V et al., PMID: 19684605). The SHOC2 gene has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variation and pathogenic missense variants are a common mechanism of disease (Gelb BD et al., PMID: 29493581). Based on available information, the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), and the RASopathy Expert Panel consensus methods (Gelb BD et al., PMID: 29493581), this variant is classified as pathogenic. |
| Palindrome, |
RCV000007223 | SCV005382615 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2024-09-24 | criteria provided, single submitter | clinical testing | |
| Clinical Genetics Laboratory, |
RCV000213000 | SCV005198234 | pathogenic | not provided | 2022-05-27 | criteria provided, single submitter | clinical testing | |
| Genomic Medicine Center of Excellence, |
RCV000007223 | SCV004805081 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2024-03-17 | criteria provided, single submitter | research | |
| Neuberg Centre For Genomic Medicine, |
RCV000007223 | SCV004171888 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | criteria provided, single submitter | clinical testing | The missense c.4A>G(p.Ser2Gly) variant in SHOC2 gene has been reported previously in individual(s) affected with Noonan syndrome with loose anagen hair (Gripp KW, et. al., 2013; Choi JH, et. al., 2015). Functional studies indicate that this variant has a damaging effect on the gene or the gene product (Cordeddu V, et. al., 2009). The p.Ser2Gly variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been submitted to ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Ser2Gly in SHOC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 2 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. | |
| Institute for Medical Genetics and Human Genetics, |
RCV003330311 | SCV004037443 | pathogenic | Pectus excavatum; Noonan syndrome-like disorder with loose anagen hair 1 | criteria provided, single submitter | not provided | ||
| Division of Human Genetics, |
RCV000007223 | SCV004024492 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2023-07-01 | criteria provided, single submitter | research | |
| Athena Diagnostics | RCV000213000 | SCV002817221 | pathogenic | not provided | 2020-05-15 | criteria provided, single submitter | clinical testing | This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene (PMID: 19684605, 25846317, 25331583, 25123707). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 19684605, 22606262).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. |
| Victorian Clinical Genetics Services, |
RCV000007223 | SCV002767174 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2025-07-01 | criteria provided, single submitter | clinical testing | This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD (v4) <0.001 for a dominant condition (6 heterozygotes, 0 homozygotes); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic for Noonan syndrome-like disorder with loose anagen hair 1 by the ClinGen RASopathy Variant Curation Expert Panel in ClinVar, and is reported in de novo individuals in the literature with RASopathy (PMID: 25331583); This variant has moderate functional evidence supporting abnormal protein function. Functional studies have demonstrated this variant causes impaired nuclear translocation and MAPK activation (PMID: 19684605); This variant has been shown to be de novo in the proband by trio analysis (parental status confirmed). Additional information: Variant is predicted to result in a missense amino acid change from serine to glycine; This variant is heterozygous; This gene is associated with autosomal dominant disease; Variant is not located in an established domain, motif, hotspot or informative constraint region; Missense variant with conflicting in silico predictions and uninformative conservation; Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome-like with loose anagen hair (MIM#607721). Missense variants in this gene result in enhanced MAPK activation (OMIM, PMID: 19684605). |
| Genomic Medicine Lab, |
RCV000007223 | SCV002576361 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | criteria provided, single submitter | clinical testing | ||
| Laboratorio de Genetica e Diagnostico Molecular, |
RCV000007223 | SCV002512520 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2021-08-16 | criteria provided, single submitter | clinical testing | ACMG classification criteria: PS2 very strong, PS3 moderate, PS4 moderate, PM2 moderate, PP2 supporting |
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV002221469 | SCV002499159 | pathogenic | Polycystic kidney disease 4 | 2022-03-30 | criteria provided, single submitter | clinical testing | PS2, PS4, PM2 |
| Genome Diagnostics Laboratory, |
RCV001813181 | SCV002060971 | pathogenic | Noonan syndrome and Noonan-related syndrome | 2021-01-08 | criteria provided, single submitter | clinical testing | |
| CENTOGENE Gmb |
RCV000007223 | SCV002059626 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2021-01-13 | criteria provided, single submitter | clinical testing | |
| 3billion | RCV000007223 | SCV002012001 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2025-01-08 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 29493581). Missense variant. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19684605). In silico tool predictions suggest damaging effect of the variant on gene or gene product [3Cnet: 0.80 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006821 /PMID: 19684605 /3billion dataset). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 19684605, 21548061, 22528146, 23918763). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 24458587, 25563136). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
| Dubai Health Genomic Medicine Center, |
RCV000007223 | SCV001984384 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2021-02-18 | criteria provided, single submitter | clinical testing | |
| Laboratory of Medical Genetics, |
RCV000007223 | SCV001976983 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2021-10-01 | criteria provided, single submitter | clinical testing | PS2, PM2, PP3, PP5 |
| Mayo Clinic Laboratories, |
RCV000213000 | SCV001714366 | pathogenic | not provided | 2019-09-09 | criteria provided, single submitter | clinical testing | PS2, PS3, PS4, PM6_Strong, PM1, PP2 |
| Institute of Medical Genetics and Applied Genomics, |
RCV000213000 | SCV001447732 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
| Centre for Mendelian Genomics, |
RCV000007223 | SCV001367708 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2018-11-21 | criteria provided, single submitter | clinical testing | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PP2,PP3,PP4,PP5. |
| Ce |
RCV000213000 | SCV001246712 | pathogenic | not provided | 2022-01-01 | criteria provided, single submitter | clinical testing | |
| Rady Children's Institute for Genomic Medicine, |
RCV000853278 | SCV000996110 | pathogenic | Noonan syndrome-like disorder with loose anagen hair | 2018-02-22 | criteria provided, single submitter | clinical testing | This variant has been previously reported as a de novo change in multiple unrelated patients with Noonan-like syndrome with loose anagen hair (PMID: 19684605, 25331583). This variant has been classified in ClinVar as pathogenic by the ClinGen Rasopathy Expert Panel and by several clinical diagnostic laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/6821/). It is present in one heterozygote in the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, this variant is classified as pathogenic. |
| Equipe Genetique des Anomalies du Developpement, |
RCV000007223 | SCV000965711 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2015-01-01 | criteria provided, single submitter | clinical testing | |
| Laboratory of Molecular Genetics |
RCV000213000 | SCV000920499 | pathogenic | not provided | 2018-07-19 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV000007223 | SCV000807267 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2021-02-16 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV006276134 | SCV000741813 | pathogenic | Cardiovascular phenotype | 2025-10-01 | criteria provided, single submitter | clinical testing | The c.4A>G (p.S2G) alteration is located in exon 2 (coding exon 1) of the SHOC2 gene. This alteration results from an A to G substitution at nucleotide position 4, causing the serine (S) at amino acid position 2 to be replaced by a glycine (G). Based on data from gnomAD, this allele has an overall frequency of 0.003% (1/31384) total alleles studied. The highest observed frequency was 0.007% (1/15428) of European (non-Finnish) alleles. This variant was reported in individual(s) with features consistent with SHOC2-related RASopathy; in at least one individual, it was determined to be de novo (Cordeddu, 2009; Capalbo, 2012; Gripp, 2013; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.S2G alteration introduces an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation (Cordeddu, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000149834 | SCV000699328 | pathogenic | RASopathy | 2019-10-26 | criteria provided, single submitter | clinical testing | Variant summary: SHOC2 c.4A>G (p.Ser2Gly) results in a non-conservative amino acid change in the encoded protein sequence, located in the N-terminal region. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248040 control chromosomes. The variant has been reported in literature as one of the most recurrent mutations found in patients with NS or NS-related disorders. It is predominantly found in patients with Noonan-like syndrome with loose anagen hair. The variant was proven to be de novo in multiple patients strongly supporting its pathogenicity. From functional studies this variant was found to introduce an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. Expression of SHOC2-S2G in vitro enhanced MAPK activation in a cell type specific fashion. Induction of SHOC2-S2G in Caenorhabditis elegans engendered protruding vulva, a neomorphic phenotype associated with aberrant signaling (Cordeddu_2009). In other functional study, the SHOC2-S2G mutant did not rescue ERK1/2 activation in Shoc2-depleted cells and the mutant was not located in late endosomes, however it was present on the plasma membrane and early endosomes (Galperin_2012). 13 clinical diagnostic laboratories (including one expert panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Fulgent Genetics, |
RCV000007223 | SCV000611318 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2017-05-18 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV000007223 | SCV000605107 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2023-12-15 | criteria provided, single submitter | clinical testing | The SHOC2 c.4A>G; p.Ser2Gly variant (rs267607048) has been reported in multiple individuals diagnosed with Noonan-like syndrome with loose anagen hair, and often identified as a de novo alteration (Cordeddu 2009, Komatsuzaki 2010, Ekvall 2011, Gripp 2013, Baldassare 2014). Functional characterization of the p.Ser2Gly protein indicates enhanced myristoylation, and aberrant targeting of the SHOC2 to the cell membrane in the absence of growth factor signaling (Cordeddu 2009). This results in an increase in basal and growth-factor stimulated ERK phosphorylation (Cordeddu 2009), consistent with the established disease mechanisms. The variant is classified as pathogenic by many sources in the ClinVar database (Variation ID: 6821) is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is classified as pathogenic. References: Baldassarre G et al. Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation. Am J Med Genet A. 2014 Dec;164A(12):3120-5. PMID: 25331583. Cordeddu V et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009 Sep;41(9):1022-6. PMID: 19684605. Ekvall S et al. Co-occurring SHOC2 and PTPN11 mutations in a patient with severe/complex Noonan syndrome-like phenotype. Am J Med Genet A. 2011 Jun;155A(6):1217-24. PMID: 21548061. Gripp KW et al. Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis. Am J Med Genet A. 2013 Oct;161A(10):2420-30. PMID: 23918763. Komatsuzaki S et al. Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies. J Hum Genet. 2010 Dec;55(12):801-9. PMID: 20882035. |
| Eurofins Ntd Llc |
RCV000213000 | SCV000332269 | pathogenic | not provided | 2015-06-15 | criteria provided, single submitter | clinical testing | |
| Hudson |
RCV000007223 | SCV000265524 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2014-09-11 | criteria provided, single submitter | research | |
| Blueprint Genetics | RCV000208379 | SCV000264222 | pathogenic | Noonan syndrome | 2015-01-26 | criteria provided, single submitter | clinical testing | |
| Molecular Diagnostics Lab, |
RCV000007223 | SCV000263045 | likely pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2015-07-20 | criteria provided, single submitter | clinical testing | |
| UCLA Clinical Genomics Center, |
RCV000007223 | SCV000255466 | likely pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2013-11-26 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000149834 | SCV000253914 | pathogenic | RASopathy | 2026-01-09 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 2 of the SHOC2 protein (p.Ser2Gly). This variant is present in population databases (rs267607048, gnomAD 0.007%). This missense change has been observed in individual(s) with Noonan-like syndrome with loose anagen hair (PMID: 19684605, 20882035, 22995099, 23918763, 25123707, 25331583). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 6821). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SHOC2 function (PMID: 19684605, 22606262). For these reasons, this variant has been classified as Pathogenic. |
| Genetic Services Laboratory, |
RCV000007223 | SCV000248876 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2015-03-13 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000213000 | SCV000209051 | pathogenic | not provided | 2020-05-18 | criteria provided, single submitter | clinical testing | Located in the critical functional domain S2 and inhibits SHOC2 function by impairing proper cellular localization of the protein (Galperin et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25858597, 22419608, 26350204, 24803665, 31501239, 19684605, 22606262, 25846317, 25563136, 21548061, 24033266, 25326637, 24458596, 24458587, 25331583, 23918763, 25123707, 26096762, 22528146, 26607044, 26519477, 20882035, 22995099, 28680615, 28554332, 24124081, 29737035, 29948256, 30732632, 30240112, 30417923, 30050098, 29907801, 31219622, 30962759, 31584751, 31628766, 31019026, 32005694, 33318624, 34008892, 33300679, 33502061, 32978145, 33240318, 32870709, 34006472, 31785789) |
| Laboratory for Molecular Medicine, |
RCV000208379 | SCV000062456 | pathogenic | Noonan syndrome | 2014-12-03 | criteria provided, single submitter | clinical testing | The p.Ser2Gly variant in SHOC2 is an established pathogenic variant for Noonan s yndrome with loose anagen hair. The variant was identified in >40 affected indiv iduals across multiple studies and in multiple cases was shown to be de novo (Co rdeddu 2009, Komatsuzaki 2010, Gripp 2013, LMM data). It has not been identified large population studies. In vitro functional studies provide some evidence tha t the p.Ser2Gly variant impacts protein function (Cordeddu 2009). In summary, th is variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner. |
| Prevention |
RCV004752691 | SCV005350870 | pathogenic | SHOC2-related disorder | 2024-07-25 | no assertion criteria provided | clinical testing | The SHOC2 c.4A>G variant is predicted to result in the amino acid substitution p.Ser2Gly. This variant was initially identified in four unrelated individuals with Noonan-like syndrome, three of which were confirmed to be de novo events (Cordeddu et al. 2009. PubMed ID: 19684605), and has since been repeatedly documented as pathogenic in multiple unrelated individuals (Cordeddu et al. 2009. PubMed ID: 19684605; Hoban et al. 2012. PubMed ID: 22528146; Bessis et al. 2019. PubMed ID: 30417923; Leach et al. 2019. PubMed ID: 29907801). Functional studies found that this variant results in aberrant targeting of SHOC2 protein to the plasma membrane, impaired translocation to the nucleus upon growth factor stimulation, and enhanced MAPK activation in a cell type specific manner (Cordeddu et al. 2009. PubMed ID: 19684605). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as pathogenic by multiple labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/6821/). This variant is interpreted as pathogenic. |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000213000 | SCV001967844 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000213000 | SCV001959945 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Baylor Genetics | RCV000149834 | SCV000196678 | pathogenic | RASopathy | no assertion criteria provided | clinical testing | Variant classified using ACMG guidelines | |
| Institute of Molecular Pathology and Immunology of the University of Porto |
RCV000007223 | SCV000143830 | not provided | Noonan syndrome-like disorder with loose anagen hair 1 | no classification provided | not provided | ||
| OMIM | RCV000007223 | SCV000027419 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 1 | 2013-10-01 | no assertion criteria provided | literature only |