ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.1310T>C (p.Ile437Thr) (rs397517150)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000038516 SCV000206728 pathogenic Noonan syndrome 2013-08-23 no assertion criteria provided clinical testing
Blueprint Genetics RCV000159164 SCV000927234 pathogenic not provided 2017-04-20 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000159164 SCV000704591 pathogenic not provided 2016-12-14 criteria provided, single submitter clinical testing
GeneDx RCV000159164 SCV000209109 pathogenic not provided 2018-12-11 criteria provided, single submitter clinical testing The I437T variant has been published in association with Noonan syndrome, including an apparently de novo occurrence (Lepri et al., 2011; Lepri et al., 2014). The variant has also been observed at GeneDx to occur apparently de novo. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). I437T is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (I437N) and in nearby residues (W432R, E433K, G434R, C441Y) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000474085 SCV000918268 pathogenic Rasopathy 2018-10-29 criteria provided, single submitter clinical testing Variant summary: SOS1 c.1310T>C (p.Ile437Thr) results in a non-conservative amino acid change located in the plekstrin homology domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. A different variant at this same codon position has been classified as pathogenic in ClinVar (Ile437Ser), indicating the location to be a potential hotspot. The variant was absent in 245614 control chromosomes (gnomAD). The variant, c.1310T>C, has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions, and in at least one case was reported as a de novo mutation (Lepri_2011, Prasad_2018). Another clinical lab reported the variant in several individuals with clinical features of Noonan syndrome as well as segregation with disease in 4 affected relatives from 2 families (LMM data via ClinVar). These data indicate that the variant is associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000474085 SCV000553267 pathogenic Rasopathy 2018-06-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 437 of the SOS1 protein (p.Ile437Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with clinical features of Noonan syndrome (PMID: 21387466, 24451042). In one of these individuals, the variant was shown to arise de novo (PMID: 21387466). ClinVar contains an entry for this variant (Variation ID: 45345), including a report of co-segregation in multiple affected individuals. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038516 SCV000062194 pathogenic Noonan syndrome 2014-05-12 criteria provided, single submitter clinical testing The p.Ile437Thr variant in SOS1 has been reported in two individuals with clinic al features of Noonan syndrome and was determined to have occurred de novo in on e of them (Lepri 2011). In addition, this variant has been identified by our lab oratory in >5 individuals with clinical features of Noonan syndrome and segregat ed with disease in 4 affected relatives from 2 families (LMM data). This variant was absent from large population studies. In summary, this variant meets criter ia to be classified as pathogenic for Noonan syndrome in an autosomal dominant m anner.

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