Submissions for variant NM_006939.4(SOS2):c.3602A>G (p.His1201Arg)

gnomAD frequency: 0.00061  dbSNP: rs555945363

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001514361	SCV001722189	benign	Noonan syndrome 9	2023-12-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001532949	SCV001748765	benign	not specified	2021-06-21	criteria provided, single submitter	clinical testing	Variant summary: SOS2 c.3602A>G (p.His1201Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 250860 control chromosomes, predominantly at a frequency of 0.005 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2000 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS2 causing Noonan Syndrome phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.3602A>G in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its 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. One laboratory classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813601	SCV002060677	benign	Noonan syndrome and Noonan-related syndrome	2020-12-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001514361	SCV002762985	benign	Noonan syndrome 9		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004037925	SCV004053023	likely benign	Cardiovascular phenotype	2023-09-08	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.
Breakthrough Genomics, Breakthrough Genomics	RCV004715442	SCV005288756	benign	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV003908825	SCV004719614	benign	SOS2-related disorder	2021-04-15	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).