Submissions for variant NM_005633.4(SOS1):c.3601C>T (p.Arg1201Trp)

dbSNP: rs752395541

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000681122	SCV000808580	likely benign	not provided	2018-03-30	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780753	SCV000918266	uncertain significance	not specified	2018-09-24	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.3601C>T (p.Arg1201Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246058 control chromosomes (gnomAD). 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.3601C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001868304	SCV002222403	uncertain significance	RASopathy	2022-06-13	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 561742). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32603605). This variant is present in population databases (rs752395541, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1201 of the SOS1 protein (p.Arg1201Trp).
Ambry Genetics	RCV002458193	SCV002617397	uncertain significance	Cardiovascular phenotype	2022-06-17	criteria provided, single submitter	clinical testing	The p.R1201W variant (also known as c.3601C>T), located in coding exon 23 of the SOS1 gene, results from a C to T substitution at nucleotide position 3601. The arginine at codon 1201 is replaced by tryptophan, an amino acid with dissimilar properties. This variant co-occurred with a variant in the MYH6 gene in a family with dilated cardiomyopathy and arrhythmia, and in vitro studies indicated this variant increased phosphorylated ERK expression (Cowan JR et al. Circ Genom Precis Med, 2020 08;13:e002892). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
University of Washington Center for Mendelian Genomics, University of Washington	RCV001543370	SCV001761928	uncertain significance	Primary dilated cardiomyopathy		no assertion criteria provided	research