ClinVar Miner

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

gnomAD frequency: 0.00039  dbSNP: rs61755043
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Total submissions: 8
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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)
Labcorp Genetics (formerly Invitae), Labcorp 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.
Breakthrough Genomics, Breakthrough Genomics RCV000429580 SCV005228653 likely benign not provided criteria provided, single submitter not provided

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