ClinVar Genomic variation as it relates to human health

The M173V variant has been reported as a de novo variant in association with a RASopathy (Kuechler et al., 2012). Another variant at this residue, M173I, has been published in association with a RASopathy and in vitro functional studies demonstrated that the variant results in altered SHOC2 function; however, this variant was inherited from a parent lacking clear RASopathy-specific clinical features (Hannig et al., 2014). Similar functional studies still have to be performed for the M173V variant to confirm a similar consequence. In addition, the only well-defined pathogenic variant in the SHOC2 gene known to cause a RASopathy is c.4 A>G (p.Ser2Gly), which results in altered protein localization rather than function (Cordeddu et al., 2009; Lee et al., 2011). The M173V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M173V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. This variant has been observed to be apparently de novo at GeneDx. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

Variant summary: SHOC2 c.517A>G (p.Met173Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250232 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.517A>G has been reported as a de novo variant in one individual affected with Noonan-like Syndrome With Loose Anagen Hair (Kuechler_2012). This variant has been also observed as apparently de novo in clinical testing (ClinVar 373090). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. In addition, another variant affecting the same codon (p.M173I) has been reported to associate with Rasopathy (HGMD database). Based on the evidence outlined above, the variant was classified as likely pathogenic.

This missense change has been observed in individual(s) with Noonan-like syndrome with loose anagen hair (PMID: 22670144). In at least one individual the variant was observed to be de novo. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Met173 amino acid residue in SHOC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25137548, 29907801, 30348783; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 SHOC2 protein function. ClinVar contains an entry for this variant (Variation ID: 373090). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 173 of the SHOC2 protein (p.Met173Val).

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 with loose anagen hair 1 (MIM#607721). Missense variants in this gene result in enhanced MAPK activation (OMIM, PMID: 19684605). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated leucine rich repeat domain (DECIPHER). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. c.519G>A; p.(Met173Ile) has been reported as a VUS by an expert panel in ClinVar, and also as likely pathogenic/pathogenic. c.519G>T; p.(Met173Ile) has been reported as a VUS in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as de novo in two individuals with a RASopathy (PMID: 22670144, ClinVar-GeneDx). This variant has been reported multiple times as likely pathogenic in ClinVar and once as a VUS. (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies showed increased stimulus-dependent MAPK signalling and enhanced binding of SHOC2 to MRAS and PPP1CB (PMID: 35348676). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The SHOC2 c.517A>G variant is predicted to result in the amino acid substitution p.Met173Val. This variant has been reported as de novo in an individual with a Noonan-like RASopathy known as Mazzanti syndrome (Motta et al. 2022. PubMed ID: 35348676). Alternate substitutions of this amino acid (p.Met173Ile and p.Met173_Leu174delinsIlePhe) have also been reported in individuals with Noonan-like syndrome (Hannig et al. 2014. PubMed ID: 25137548; Motta et al. 2022. PubMed ID: 35348676). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic.