Submissions for variant NM_005633.4(SOS1):c.2165G>A (p.Arg722Lys)

gnomAD frequency: 0.00010  dbSNP: rs142666652

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552706	SCV000659134	uncertain significance	RASopathy	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 722 of the SOS1 protein (p.Arg722Lys). This variant is present in population databases (rs142666652, gnomAD 0.03%). 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: 477718). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175591	SCV001339235	likely benign	not specified	2020-03-10	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.2165G>A (p.Arg722Lys) results in a conservative amino acid change located in the Ras-like guanine nucleotide exchange factor, N-terminal domain (IPR000651) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 250558 control chromosomes, predominantly at a frequency of 0.00023 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 7.7- fold the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome and Related Conditions phenotype (3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2165G>A in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating an impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198922	SCV001369917	uncertain significance	Fibromatosis, gingival, 1	2020-02-27	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BS2.
Ambry Genetics	RCV002431722	SCV002727373	likely benign	Cardiovascular phenotype	2019-07-19	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.
CeGaT Center for Human Genetics Tuebingen	RCV003884642	SCV004698650	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	SOS1: BS1
Clinical Genomics Laboratory, Stanford Medicine	RCV001198922	SCV004803174	uncertain significance	Fibromatosis, gingival, 1	2021-06-04	criteria provided, single submitter	clinical testing	• The p.Arg722Lys variant in the SOS1 gene has not been previously reported in association with disease. • This variant has been identified in 31/128,362 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). • Computational tools predict that this variant does not impact protein function; however, the accuracy of in silico algorithms is limited. • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Arg722Lys variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: BP4]