Submissions for variant NM_006939.4(SOS2):c.2317G>C (p.Asp773His)

gnomAD frequency: 0.00041  dbSNP: rs114711076

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000417876	SCV000511319	likely benign	not provided	2016-10-11	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085844	SCV000774701	likely benign	Noonan syndrome 9	2024-01-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328386	SCV001519509	likely benign	not specified	2021-03-01	criteria provided, single submitter	clinical testing	Variant summary: SOS2 c.2317G>C (p.Asp773His) 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 0.00014 in 251282 control chromosomes. The observed variant frequency is approximately 54 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.2317G>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 likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001085844	SCV002049930	likely benign	Noonan syndrome 9	2020-10-12	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001085844	SCV002763042	likely benign	Noonan syndrome 9		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004022272	SCV005025074	benign	Cardiovascular phenotype	2023-11-27	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001261126	SCV001438533	likely benign	Noonan syndrome		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003950337	SCV004758299	likely benign	SOS2-related disorder	2021-10-19	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).