Submissions for variant NM_005633.4(SOS1):c.698A>G (p.Asn233Ser)

gnomAD frequency: 0.00026  dbSNP: rs144934321

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000521733	SCV000616522	likely benign	RASopathy	2017-04-18	reviewed by expert panel	curation	The filtering allele frequency of the c.698A>G (p.Asn233Ser) variant in the SOS1 gene is 0.0393% (8/10108) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581)
Eurofins Ntd Llc (ga)	RCV000724504	SCV000231086	uncertain significance	not provided	2014-12-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000724504	SCV000491015	benign	not provided	2019-03-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201323	SCV001372467	likely benign	not specified	2020-06-29	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.698A>G (p.Asn233Ser) results in a conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) 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 4.4e-05 in 250876 control chromosomes, predominantly at a frequency of 0.00062 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 21-fold of 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 African or African-American origin. To our knowledge, no occurrence of c.698A>G in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance while, the ClinGen RASopathy Variant Curation Expert Panel (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000521733	SCV001703952	likely benign	RASopathy	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362921	SCV002665160	likely benign	Cardiovascular phenotype	2019-06-24	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.
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001261071	SCV001438473	uncertain significance	Noonan syndrome		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003967436	SCV004782131	likely benign	SOS1-related disorder	2020-05-11	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).