Submissions for variant NM_017617.5(NOTCH1):c.7369C>G (p.Leu2457Val)

gnomAD frequency: 0.00039  dbSNP: rs61755043

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000429580	SCV000518462	likely benign	not provided	2019-08-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22086416)
Invitae	RCV000554225	SCV000659492	benign	Adams-Oliver syndrome 5	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313051	SCV000738426	benign	Familial thoracic aortic aneurysm and aortic dissection	2016-11-01	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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660180	SCV000782174	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000554225	SCV002553771	benign	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270257	SCV002553772	benign	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479113	SCV004223199	benign	not specified	2023-11-27	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.7369C>G (p.Leu2457Val) results in a conservative amino acid change located in the Notch, C-terminal domain (IPR024600) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00064 in 217572 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 1022.19 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 phenotype (6.3e-07), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.7369C>G in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.