Total submissions: 29
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004732471 | SCV005367861 | pathogenic | RASopathy | 2024-09-17 | reviewed by expert panel | curation | The c.146C>G (Pro49Arg) variant in PPP1CB is a missense variant predicted to cause substitution of proline by arginine at amino acid 49. This variant is absent from gnomAD v4 (PM2_Supporting). PPP1CB, in which the variant was identified, is defined by the ClinGen RASopathy VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The missense Z-score is 4.33 which is above the threshold set by the Rasopathy VCEP. The computational predictor REVEL gives a score of 0.438, which is neither above nor below the thresholds predicting a damaging or benign impact on PPP1CB function. This variant has been reported in 13 probands with features of RASopathy (PS4; PMIDs: 27264673, 27681385, 27868344, 28211982, 30368668, 32476286). This variant has been identified as a de novo occurrence with confirmed parental relationships in 9 individuals and as a de novo occurrence with unconfirmed parental relationships in 2 individuals with features of RASopathy (PS2_VeryStrong; PMIDs: 27264673, 27681385, 27868344). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2_VS, PS4, PM2_P, PP2. (RASopathy VCEP specifications version 1.1; 9/17/2024) |
| Center of Human Genetics, |
RCV000490622 | SCV006076751 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 2 | 2025-01-01 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV005260026 | SCV005922537 | pathogenic | Cardiovascular phenotype | 2025-03-04 | criteria provided, single submitter | clinical testing | The p.P49R pathogenic mutation (also known as c.146C>G), located in coding exon 2 of the PPP1CB gene, results from a C to G substitution at nucleotide position 146. The proline at codon 49 is replaced by arginine, an amino acid with dissimilar properties. This variant was reported in individual(s) with features consistent with PPP1CB-related Noonan syndrome-like disorder with loose anagen hair; in at least one individual, it was determined to be de novo (Ma L et al. Hum Genet, 2016 Dec;135:1399-1409; Gripp KW et al. Am J Med Genet A, 2016 Sep;170:2237-47; Zambrano RM et al. Am J Med Genet A, 2017 Feb;173:565-567; Bertola D et al. Am J Med Genet A, 2017 Mar;173:824-828; Turner TN et al. Am J Hum Genet, 2019 Dec;105:1274-1285; Giugliano T et al. Genes (Basel), 2019 Jul;10). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. |
| Molecular Genetics Laboratory, |
RCV000490622 | SCV005367958 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 2 | 2024-07-09 | criteria provided, single submitter | clinical testing | |
| Rady Children's Institute for Genomic Medicine, |
RCV000490622 | SCV004046312 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 2 | criteria provided, single submitter | clinical testing | This variant has been previously reported as a de novo heterozygous variant in multiple unrelated individuals with Noonan-like syndrome with loose anagen hair (PMID: 27264673, 27681385, 27868344, 28211982, 31474318). It is absent from the gnomAD population database and thus is presumed to be rare. The c.146C>G (p.Pro49Arg) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.146C>G (p.Pro49Arg) variant is classified as Pathogenic. | |
| Department of Endocrinology and Genetics, |
RCV000490622 | SCV002574761 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 2 | 2022-09-08 | criteria provided, single submitter | clinical testing | |
| Centre de Biologie Pathologie Génétique, |
RCV002274002 | SCV002559115 | pathogenic | Neurodevelopmental delay | criteria provided, single submitter | clinical testing | ||
| Victorian Clinical Genetics Services, |
RCV000490622 | SCV002557913 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 2 | 2023-07-17 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome-like disorder with loose anagen hair 2 (MIM#617506) (PMID: 30348783). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent variant reported in multiple individuals with Noonan syndrome-like disorder with loose anagen hair 2 (MIM#617506) (ClinVar, DECIPHER, PMID: 33491856). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| 3billion | RCV000490622 | SCV002011951 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 2 | 2023-06-01 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.75). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000254648 /PMID: 27264673 /3billion dataset). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 27264673, 28211982). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 27264673, 27681385, 28211982). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
| Laboratory of Medical Genetics, |
RCV000490622 | SCV001976798 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 2 | 2021-10-05 | criteria provided, single submitter | clinical testing | PM2, PP2, PP3, PP5 |
| Ce |
RCV000257986 | SCV001962241 | pathogenic | not provided | 2023-04-01 | criteria provided, single submitter | clinical testing | PPP1CB: PS2, PM2, PS4:Moderate, PP2, PP4 |
| Institute of Medical Genetics and Applied Genomics, |
RCV000257986 | SCV001447547 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV001265940 | SCV001444112 | pathogenic | Inborn genetic diseases | 2016-07-06 | criteria provided, single submitter | clinical testing | |
| Equipe Genetique des Anomalies du Developpement, |
RCV000490622 | SCV001190249 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 2 | 2019-05-04 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000257986 | SCV000933113 | pathogenic | not provided | 2024-08-15 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 49 of the PPP1CB protein (p.Pro49Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome-like disorder with loose anagen hair (NSLDH) (PMID: 27264673, 27681385, 27868344, 28211982). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 254648). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PPP1CB protein function. For these reasons, this variant has been classified as Pathogenic. |
| Blueprint Genetics | RCV000257986 | SCV000928041 | pathogenic | not provided | 2018-11-07 | criteria provided, single submitter | clinical testing | |
| Eurofins Ntd Llc |
RCV000257986 | SCV000861880 | pathogenic | not provided | 2018-06-15 | criteria provided, single submitter | clinical testing | |
| Center for Pediatric Genomic Medicine, |
RCV000257986 | SCV000609586 | pathogenic | not provided | 2017-08-30 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000257986 | SCV000299373 | pathogenic | not provided | 2021-10-05 | criteria provided, single submitter | clinical testing | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27264673, 27868344, 27338287, 28211982, 27681385, 28135719, 30368668, 31474318, 31370276, 32476286) |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000257986 | SCV001971001 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000257986 | SCV001956324 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Laboratory of Diagnostic Genome Analysis, |
RCV000257986 | SCV001798142 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Diagnostic Laboratory, |
RCV000257986 | SCV001744847 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Coyote Medical Laboratory |
RCV000490622 | SCV001441279 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 2 | 2018-05-28 | no assertion criteria provided | clinical testing | |
| Lupski Lab, |
RCV000490622 | SCV001438015 | likely pathogenic | Noonan syndrome-like disorder with loose anagen hair 2 | 2018-06-29 | no assertion criteria provided | research | |
| University of Washington Center for Mendelian Genomics, |
RCV001257999 | SCV001434812 | likely pathogenic | Dandy-Walker syndrome | no assertion criteria provided | research | ||
| Centre de Biologie Pathologie Génétique, |
RCV000490622 | SCV001428110 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 2 | 2019-01-01 | no assertion criteria provided | clinical testing | |
| Service de Génétique Moléculaire, |
RCV001251211 | SCV001426696 | pathogenic | Noonan syndrome | no assertion criteria provided | clinical testing | ||
| OMIM | RCV000490622 | SCV000579309 | pathogenic | Noonan syndrome-like disorder with loose anagen hair 2 | 2017-05-31 | no assertion criteria provided | literature only |