Submissions for variant NM_017617.5(NOTCH1):c.6836C>T (p.Ala2279Val)

gnomAD frequency: 0.00061  dbSNP: rs200370953

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522367	SCV000619086	uncertain significance	not specified	2017-07-13	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the NOTCH1 gene. The A2279V variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 0.15-0.21% alleles from individuals of African ancestry in large population cohorts, indicating it may be a rare benign variant in this population (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A2279V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is only conserved in mammals. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae	RCV000655274	SCV000777204	likely benign	Adams-Oliver syndrome 5	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002367736	SCV002666645	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2021-08-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Revvity Omics, Revvity	RCV003133303	SCV003815974	uncertain significance	not provided	2019-11-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003925561	SCV004740697	likely benign	NOTCH1-related condition	2019-10-11	criteria provided, single submitter	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).