ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.826G>A (p.Val276Met)

gnomAD frequency: 0.00004  dbSNP: rs369721921
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001237666 SCV001410434 uncertain significance Adams-Oliver syndrome 5 2024-07-22 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 276 of the NOTCH1 protein (p.Val276Met). This variant is present in population databases (rs369721921, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 134960). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV001562983 SCV001785842 uncertain significance not provided 2023-03-15 criteria provided, single submitter clinical testing Has not been previously published in association with connective tissue disorders as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24728327)
Genome-Nilou Lab RCV001237666 SCV002553981 uncertain significance Adams-Oliver syndrome 5 2022-03-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002269869 SCV002553982 uncertain significance Aortic valve disease 1 2022-03-15 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002483224 SCV002787503 uncertain significance Aortic valve disease 1; Adams-Oliver syndrome 5 2022-01-12 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004528834 SCV004107415 uncertain significance NOTCH1-related disorder 2022-10-01 criteria provided, single submitter clinical testing The NOTCH1 c.826G>A variant is predicted to result in the amino acid substitution p.Val276Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0027% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-139413934-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
ITMI RCV000121710 SCV000085908 not provided not specified 2013-09-19 no assertion provided reference population

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