ClinVar Genomic variation as it relates to human health

The c.806T>C (p.Met269Thr) variant in SOS1 has been reported in the literature in at least 2 unconfirmed and 1 confirmed de novo occurrences in patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 17586837; 19953625, 20683980). It has also been reported as a confirmed de novo occurrence in a patient with clinical features of a RASoapthy (PMID: 20683980). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is in SOS1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Met269Thr variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PP2, PP3, PM1, PM2, PS2_VeryStrong.

A heterozygous missense variation in exon 6 of the SOS1 gene (chr2:g.39051202A>C;) that result in the amino acid substitution of Arginine for Methionine at codon 269 (p.Met269Arg; ENST00000402219.8) was detected. thep.Met269Arg variant has not been reported in the 1000 genomes, gnomAD and our internal databases. the in silico predictions of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT AND Mutation Taster2. the reference codon is conserved across species.

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic; This variant is associated with the following publications: (PMID: 19953625, 31560489, 30417923, 20683980, 24803665, 19020799, 21387466, 26280111, 17586837, 29037749, 31589614, 33300679, 29493581, 17143282, 20648242, 12628188)

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 269 of the SOS1 protein (p.Met269Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17586837, 19953625, 20683980, 21387466). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40662). 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 expected to disrupt SOS1 protein function with a positive predictive value of 95%. This variant disrupts the p.Met269 amino acid residue in SOS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17143282, 20683980, 21387466). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Child with strong clinical suspicion of Noonan syndrome. Next generation DNA sequencing of peripheral blood sample has revealed the presence of a pathogenic variant NM_005633.3(SOS1):c.806T>C in the SOS1 gene in heterozygous state.

The p.Met269Thr variant has been reported in >10 individuals with clinical featu res of Noonan syndrome (Ko 2008, Longoni 2010, Denayer 2010, Lepri 2011, Zenker 2007; LMM unpublished data). In three of these probands, the variant occurred de novo (Zenker 2007, Denayer 2010, Longoni 2010). It was absent from large popula tion studies. In summary, this variant meets our criteria to be classified as pa thogenic for Noonan syndrome in an autosomal dominant manner (http://www.partner s.org/personalizedmedicine/LMM) based upon absence from controls and de novo occ urrences.

Variant summary: SOS1 c.806T>C (p.Met269Thr) results in a non-conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251358 control chromosomes (gnomAD). c.806T>C has been reported in the literature in multiple individuals affected with Noonan Syndrome, often observed as a de novo variant (e.g. Baldassarre_2011, Denayer_2010, Longoni_2010, Koh_2019). These data indicate that the variant is very likely to be associated with disease. Nine ClinVar submitters including ClinGen RASopathy Variant Curation Expert Panel (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040662). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 19953625, 17586837, 20683980, PS2_VS). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.895>=0.6, 3CNET: 0.892>=0.75). A missense variant is a common mechanism . It is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012870,VCV000981559, PMID:17143282). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change in SOS1 is predicted to replace methionine with threonine at codon 269, p.(Met269Thr). The methionine residue is highly conserved (99/99 vertebrates, UCSC), and is located in Dbl homology domain. Met269 is a critical residue and is defined as a mutational hotspot (PMID: 29493581). There is a moderate physicochemical difference between methionine and threonine. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in multiple probands with a clinical diagnosis of Noonan syndrome, identified as a de novo occurrence with confirmed parental relationships in at least one individual and as a de novo occurrence with unconfirmed parental relationships in at least one individual (PMID: 17586837, 19020799, 1995362, 20683980, 21387466). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS2/PM6_Strong, PS4, PM1, PM2_Supporting, PP3.

The p.M269T pathogenic mutation (also known as c.806T>C), located in coding exon 6 of the SOS1 gene, results from a T to C substitution at nucleotide position 806. The methionine at codon 269 is replaced by threonine, an amino acid with similar properties. This mutation was identified in multiple individuals with Noonan syndrome, including several de novo occurrences (Zenker M et al. J Med Genet. 2007 Oct;44:651-6; Ko JM et al. J Hum Genet. 2008 Nov;53:999-1006; Denayer E et al. Genes Chromosomes Cancer. 2010 Mar;49:242-52; Longoni M et al. Am J Med Genet A. 2010 Sep;152A:2176-84; Lepri F et al. Hum Mutat. 2011 Jul;32:760-72). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.