Submissions for variant NM_017617.5(NOTCH1):c.3115G>A (p.Gly1039Ser)

gnomAD frequency: 0.00063  dbSNP: rs200207651

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002311096	SCV000319918	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2017-10-13	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.
Invitae	RCV000456603	SCV000548963	benign	Adams-Oliver syndrome 5	2024-01-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001567151	SCV001790790	likely benign	not provided	2021-02-02	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000456603	SCV002554537	benign	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270173	SCV002554539	benign	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330614	SCV004039481	benign	not specified	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.3115G>A (p.Gly1039Ser) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of 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 0.00083 in 154310 control chromosomes (gnomAD). The observed variant frequency is approximately 1300 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 (6.3e-07), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3115G>A in individuals affected with Adams-Oliver Syndrome 5 and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters have assessed the variant since 2014: two classified the variant as likely benign and two as benign. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004542948	SCV004789621	benign	NOTCH1-related disorder	2024-02-07	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).