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

dbSNP: rs397517146

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2023-11-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 34411415, 21387466, 32627323, 36959127, 30712878)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000821113	SCV000961856	pathogenic	RASopathy	2022-06-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 45344). This missense change 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 378 of the SOS1 protein (p.Thr378Ala).
Ambry Genetics	RCV002321513	SCV002609122	pathogenic	Cardiovascular phenotype	2022-07-01	criteria provided, single submitter	clinical testing	The p.T378A pathogenic mutation (also known as c.1132A>G), located in coding exon 9 of the SOS1 gene, results from an A to G substitution at nucleotide position 1132. The threonine at codon 378 is replaced by alanine, an amino acid with similar properties. This variant has been detected in multiple individuals with a clinical diagnosis or suspicion of Noonan syndrome; it has also been determined to be the result of a de novo mutation or germline mosaicism in multiple families (Denayer E et al. Genes Chromosomes Cancer, 2010 Mar;49:242-52; Ambry internal data; personal communication with other laboratories). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genome-Nilou Lab	RCV002467539	SCV002763461	likely pathogenic	Noonan syndrome 4		criteria provided, single submitter	clinical testing