Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000156537 | SCV000206256 | likely pathogenic | Noonan syndrome | 2017-04-26 | criteria provided, single submitter | clinical testing | The p.Phe623Val variant in SOS1 occurred de novo in 1 individual with clinical f eatures of a RASopathy (LMM data) and has been reported in ClinVar (Variation ID 179739). This variant was absent from large population studies. An additional a mino acid change at this position (p.Phe623Ile) was identified in two probands w ith clinical features of Noonan syndrome, which occured de novo in 1 of these in dividuals with confirmed paternity (Zenker 2007, Fabretto 2010). Computational p rediction tools and conservation analysis do not provide strong support for or a gainst an impact to the protein. In summary, although additional studies are req uired to fully establish its clinical significance, the p.Phe623Val variant is l ikely pathogenic. |
| Gene |
RCV000414349 | SCV000491061 | pathogenic | not provided | 2023-04-05 | criteria provided, single submitter | clinical testing | Observed in a proband with hypertrophic cardiomyopathy in the published literature (Baban et al., 2019); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29493581, 22589294, 31368652, 17586837, 20673819) |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000770761 | SCV000698620 | uncertain significance | not specified | 2019-02-26 | criteria provided, single submitter | clinical testing | Variant summary: SOS1 c.1867T>G (p.Phe623Val) results in a non-conservative amino acid change located in the N-terminal Ras-like guanine nucleotide exchange factor domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function (ACMG PP3). The variant was absent in 276468 control chromosomes (gnomAD) (ACMG PM2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1867T>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. However, a variant at the same codon (p.Phe623Ile) has been reported in individuals in association with Noonan syndrome, including one de novo occurrence (Fabretto_2010, Zenker_2007), suggesting the location to be important for protein function. Substitution of the Phe623 residue by another amino acid has been hypothesized to cause altered guanine nucleotide exchange activity of SOS1 and perturb the catalytic activity of the CDC25 domain (Lepri_2011, Zenker_2007) (ACMG PM5). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as likely pathogenic. One of these assessments mentions a "reportedly" de-novo occurrence of this variant in one individual with clinical features of RASopathy although we do not have independent evidence to corroborate. This variant was identified once in our laboratory in an adult female patient tested on a panel for Noonan syndrome and related disorders. A definitive clinical indication was not provided, the patient is lost to follow-up and no additional testing has been performed. Based on the evidence outlined above, the variant was classified as uncertain significance until additional information (i.e., clinical and functional studies) becomes available. |
| Invitae | RCV000793245 | SCV000932590 | pathogenic | RASopathy | 2021-08-12 | criteria provided, single submitter | clinical testing |