ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.1787C>T (p.Thr596Met)

gnomAD frequency: 0.00020  dbSNP: rs61755997
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002311202 SCV000320524 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-02-28 criteria provided, single submitter clinical testing The p.T596M variant (also known as c.1787C>T), located in coding exon 11 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 1787. The threonine at codon 596 is replaced by methionine, an amino acid with similar properties. This variant (also referred to as c.1963 C>T) was reported in a patient with bicuspid aortic valve (Mohamed SA et al, Biochem. Biophys. Res. Commun. 2006 Jul; 345(4):1460-5). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000660144 SCV000782138 likely benign Connective tissue disorder 2016-11-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001049180 SCV001213216 likely benign Adams-Oliver syndrome 5 2024-01-12 criteria provided, single submitter clinical testing
GeneDx RCV001575577 SCV001802603 likely benign not provided 2021-06-10 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17662764, 16729972)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004701355 SCV005202163 likely benign not specified 2024-07-30 criteria provided, single submitter clinical testing Variant summary: NOTCH1 c.1787C>T (p.Thr596Met) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 240946 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 4.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Aortic Valve Disease phenotype (3.1e-05). c.1787C>T has been reported in the literature in individuals affected with NOTCH1-related conditions (example: Marek Debiec_2022, Mohamed_2006). These report(s) do not provide unequivocal conclusions about association of the variant with Aortic Valve Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35288444, 16729972). ClinVar contains an entry for this variant (Variation ID: 264528). Based on the evidence outlined above, the variant was classified as likely benign.
OMIM RCV000787043 SCV000925959 pathogenic Aortic valve disease 1 2006-07-14 no assertion criteria provided literature only

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