Submissions for variant NM_005633.4(SOS1):c.3706C>A (p.Pro1236Thr)

gnomAD frequency: 0.00016  dbSNP: rs727504636

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155897	SCV000205608	benign	not specified	2014-12-30	criteria provided, single submitter	clinical testing	p.Pro1236Thr in exon 23 of SOS1: This variant is not expected to have clinical s ignificance because it was identified in 2 probands with clinical features of No onan syndrome who inherited the variant from unaffected parents, one parent car ried the variant in an apparently homozygous state (LMM unpublished data). In ad dition, 2 unaffected siblings from one of these families also carried the varian t. This variant has also been identified in 1/67696 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org).
GeneDx	RCV000680364	SCV000535444	likely benign	not provided	2020-11-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000155897	SCV001623183	uncertain significance	not specified	2024-04-11	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.3706C>A (p.Pro1236Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251168 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3706C>A in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 179112). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857535	SCV002125140	uncertain significance	RASopathy	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1236 of the SOS1 protein (p.Pro1236Thr). This variant is present in population databases (rs727504636, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 179112). 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 SOS1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291573	SCV002584609	uncertain significance	Noonan syndrome 4	2022-09-01	criteria provided, single submitter	clinical testing	The SOS1 c.3706C>A (p.Pro1236Thr) missense change has a maximum subpopulation frequency of 0.0028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with Noonan syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Ambry Genetics	RCV002345510	SCV002623330	likely benign	Cardiovascular phenotype	2020-03-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.