ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.4795G>A (p.Val1599Met)

gnomAD frequency: 0.00007  dbSNP: rs543770603
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000704495 SCV000833446 benign Adams-Oliver syndrome 5 2024-10-08 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000766057 SCV000897513 uncertain significance Aortic valve disease 1; Adams-Oliver syndrome 5 2018-10-31 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000704495 SCV002553390 uncertain significance Adams-Oliver syndrome 5 2022-03-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002270978 SCV002553391 uncertain significance Aortic valve disease 1 2022-03-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV004649288 SCV005142124 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2024-05-08 criteria provided, single submitter clinical testing The p.V1599M variant (also known as c.4795G>A), located in coding exon 26 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 4795. The valine at codon 1599 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004768592 SCV005381400 uncertain significance not specified 2024-08-05 criteria provided, single submitter clinical testing Variant summary: NOTCH1 c.4795G>A (p.Val1599Met) results in a conservative amino acid change located in the Notch, NOD domain (IPR010660) 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 2.1e-05 in 1584424 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in NOTCH1 causing Aortic Valve Disease (2.1e-05 vs 3.1e-05), allowing no conclusion about variant significance (though it does exceed the expected frequency for an Adams-Oliver disease associated variant). To our knowledge, no occurrence of c.4795G>A in individuals affected with NOTCH1-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 580837). Based on the evidence outlined above, the variant was classified as uncertain significance.

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