ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.1132A>G (p.Thr378Ala) (rs397517146)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038510 SCV000062188 likely pathogenic Noonan syndrome 2012-10-04 criteria provided, single submitter clinical testing The Thr378Ala variant in SOS1 has been previously reported in the literature in one individual with clinical features of an unspecified Noonan spectrum disorder (cohort consisted of individuals with Noonan syndrome, CFC syndrome, or nonsynd romic congenital heart defects) and was absent in 600 control chromosomes (Lepri 2011). This variant has also been observed in one individual by our laboratory and was found to have occurred de novo. Computational analyses (biochemical amin o acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that th e Thr378Ala variant may not impact the protein, though this information is not p redictive enough to rule out pathogenicity. In summary, additional information i s needed to fully assess the clinical significance of the Thr378Ala variant.
GeneDx RCV000482668 SCV000565585 pathogenic not provided 2018-09-27 criteria provided, single submitter clinical testing The T378A variant has been mentioned as an unclassified sequence variant (Lepri et al., 2011). T378A is reported as a likely pathogenic variant in ClinVar by a different clinical laboratory, where it was observed to occur apparently de novo in a patient with Noonan syndrome (ClinVar SCV000062188.4; Landrum et al., 2015). Additionally, the variant has been observed to occur apparently de novo in an affected individual and also segregate in a family with multiple affected individuals tested at GeneDx. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T378A variant 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 in the DH domain that is conserved across species, yet in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, we consider this variant to be pathogenic.
Invitae RCV000821113 SCV000961856 pathogenic Rasopathy 2020-03-03 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 378 of the SOS1 protein (p.Thr378Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 19953625, Invitae, ClinVar). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 45344). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.

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