Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000788003 | SCV000927035 | likely pathogenic | Noonan syndrome and Noonan-related syndrome | 2019-02-28 | reviewed by expert panel | curation | The c.512T>C (p.Val171Ala) variant in SOS1 has been reported as an unconfirmed de novo occurrence in a patient with clinical features of a Noonan spectrum disorder (PM6; Partners LMM internal data; GTR Lab ID: 21766; ClinVar SCV000062240.5). The p.Val171Ala variant has also been identified in another independent occurrences in patients with clinical features of a familial RASopathy (PS4_Supporting; PMID: 29402968). This variant was absent from large population studies (PM2; gnomAD, http://gnomAD.broadinstitute.org). A different pathogenic missense variant (p.Val171Gly) has been previously identified at this codon of SOS1 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 40654). The variant is located in the SOS1 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 likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PM5, PM2, PS4_Supporting, PP2. |
Laboratory for Molecular Medicine, |
RCV000038562 | SCV000062240 | likely pathogenic | Noonan syndrome | 2014-09-25 | criteria provided, single submitter | clinical testing | The Val171Ala variant in SOS1 has been previously identified in one individual w ith clinical features of a Noonan spectrum disorder and was identified to occur de novo (LMM unpublished data). It was absent from large population studies. Com putational prediction tools and conservation analysis do not provide strong supp ort for or against an impact to the protein. In summary, while the available dat a on the Val171Ala variant is suspicious to be pathogenic, the clinical signific ance of this variant is uncertain. |
Revvity Omics, |
RCV001781357 | SCV002023611 | likely pathogenic | not provided | 2020-08-31 | criteria provided, single submitter | clinical testing |