Submissions for variant NM_006939.4(SOS2):c.3830T>C (p.Leu1277Pro)

gnomAD frequency: 0.00041  dbSNP: rs146802994

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541220	SCV000656030	likely benign	Noonan syndrome 9	2024-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001584349	SCV001821362	benign	not specified	2022-09-12	criteria provided, single submitter	clinical testing	Variant summary: SOS2 c.3830T>C (p.Leu1277Pro) 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 0.00031 in 251482 control chromosomes. The observed variant frequency is approximately 126 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 benign. To our knowledge, no occurrence of c.3830T>C in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001683588	SCV001899000	benign	not provided	2021-04-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002367952	SCV002623857	likely benign	Cardiovascular phenotype	2021-12-23	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.
Genome-Nilou Lab	RCV000541220	SCV002762968	benign	Noonan syndrome 9		criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003945323	SCV004762561	likely benign	SOS2-related disorder	2019-10-31	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).