Total submissions: 18
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV002233108 | SCV006059799 | likely pathogenic | RASopathy | 2024-12-03 | reviewed by expert panel | curation | The NM_006767.4:c.848G>A variant in LZTR1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 283 (p.Arg283Gln). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.609, which is neither above nor below the thresholds predicting a damaging or benign impact on LZTR1 function. This variant has been reported in 5 probands with RASopathy (PS4_Moderate; PMID: 30368668, SCV000808536.4, GeneDx). This variant has been identified as a de novo occurrence with confirmed parental relationships in 2 individuals with RASopathy (PS2; PMID: 30368668, SCV000808536.4, GeneDx). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PS4_Moderate, PM2_Supporting. (ClinGen RASopathy VCEP specifications version 1.3; 12/3/2024) |
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV004535698 | SCV005873953 | pathogenic | LZTR1-related disorder | 2024-09-12 | criteria provided, single submitter | clinical testing | PS4, PM2, PM6_Strong, PP3 |
| Ambry Genetics | RCV004993935 | SCV005616231 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2024-10-28 | criteria provided, single submitter | clinical testing | The p.R283Q variant (also known as c.848G>A), located in coding exon 9 of the LZTR1 gene, results from a G to A substitution at nucleotide position 848. The arginine at codon 283 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in multiple probands with features consistent with autosomal dominant Noonan syndrome, including at least 2 individuals with reported de novo variants (Verberne EA et al. Am J Med Genet A, 2022 Jun;188:1777-1791; Swarts JW et al. Am J Med Genet A, 2022 Nov;188:3242-3261; Farncombe KM et al. BMC Med Genomics, 2022 Jul;15:160; Juchnewitsch AG et al. Front Endocrinol (Lausanne), 2024 Apr;15:1312357). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is likely pathogenic for autosomal dominant Noonan syndrome; however, the association of this alteration with an increased risk of LZTR1-related schwannomatosis (SWN) is unknown. |
| Baylor Genetics | RCV004568578 | SCV005060701 | pathogenic | LZTR1-related schwannomatosis | 2023-11-27 | criteria provided, single submitter | clinical testing | |
| Laan Lab, |
RCV003991581 | SCV004231717 | pathogenic | Male infertility with azoospermia or oligozoospermia due to single gene mutation | 2023-12-01 | criteria provided, single submitter | research | |
| 3billion | RCV000761304 | SCV003841632 | pathogenic | Noonan syndrome 10 | 2023-02-23 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.61; 3Cnet: 0.69). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000561716). The variant has been previously reported as de novo in a similarly affected individual (PMID: 30368668). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
| Revvity Omics, |
RCV000681082 | SCV003832268 | likely pathogenic | not provided | 2022-07-18 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000681082 | SCV003254428 | pathogenic | not provided | 2024-05-27 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 283 of the LZTR1 protein (p.Arg283Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 30368668, 33258288; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 561716). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LZTR1 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LZTR1 function (PMID: 30368668). For these reasons, this variant has been classified as Pathogenic. |
| Athena Diagnostics | RCV000681082 | SCV002817313 | pathogenic | not provided | 2024-08-22 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant segregates with disease in multiple families. This variant appears to occur de novo in one individual with clinical features associated with this gene. |
| Genome Diagnostics Laboratory, |
RCV001813545 | SCV002060780 | likely pathogenic | Noonan syndrome and Noonan-related syndrome | 2022-12-08 | criteria provided, single submitter | clinical testing | This missense variant results in a change from arginine to glutamine at amino acid position 283. It has been reported previously in individuals with Noonan syndrome (PMIDs: 30368668, 33587123) or neurological anomaly (precise phenotype not specified – PMID: 33258288). This variant was reported to have occurred de novo in at least one individual. This variant is observed at an allele frequency of 0.000062% in population controls of the Genome Aggregation Database (gnomAD). In silico prediction programs predict this variant to impact protein function. Based on the evidence above, this variant is classified as likely pathogenic (ACMG criteria - PS4_Moderate, PM6, PP3, PP5). |
| Baylor Genetics | RCV000761304 | SCV001526201 | likely pathogenic | Noonan syndrome 10 | 2018-03-19 | criteria provided, single submitter | clinical testing | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002233108 | SCV001448329 | likely pathogenic | RASopathy | 2022-04-07 | criteria provided, single submitter | clinical testing | Variant summary: LZTR1 c.848G>A (p.Arg283Gln) results in a conservative amino acid change located in the Kelch repeat type 1 domain (IPR006652) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 230510 control chromosomes (gnomAD). c.848G>A has been reported in the literature in individuals affected with Noonan Syndrome, including two individuals were the variant arose de novo (Umeki_2019, Quaio_2020) and one individual via maternal inheritance (Maron_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Umeki_2019). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance, two as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Molecular Diagnostics Laboratory, |
RCV000761304 | SCV000891281 | likely pathogenic | Noonan syndrome 10 | 2018-11-21 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000681082 | SCV000808536 | pathogenic | not provided | 2021-11-15 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30368668, 33258288, 33792302) |
| Prevention |
RCV004535698 | SCV004106725 | likely pathogenic | LZTR1-related disorder | 2023-11-21 | no assertion criteria provided | clinical testing | The LZTR1 c.848G>A variant is predicted to result in the amino acid substitution p.Arg283Gln. This variant was reported de novo in two individuals with Noonan syndrome (Umeki et al. 2019. PubMed ID: 30368668; supplementary material, Quaio et al. 2020. PubMed ID: 33258288). This variant was also reported as maternally-inherited in an individual with Noonan syndrome (eTable 2, Maron et al. 2021. PubMed ID: 33587123). In vitro functional studies showed that this variant does not induce the activation of ERK- or ELK-mediated transactivation (Figure S2, Umeki et al. 2019. PubMed ID: 30368668). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. |
| Division of Human Genetics, |
RCV003151134 | SCV003840171 | likely pathogenic | Noonan syndrome 1 | no assertion criteria provided | research | ||
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000681082 | SCV001956355 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Clinical Genetics, |
RCV000681082 | SCV001917340 | likely pathogenic | not provided | no assertion criteria provided | clinical testing |