ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.4010C>G (p.Pro1337Arg)

gnomAD frequency: 0.00001  dbSNP: rs1043832212
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481924 SCV000572747 uncertain significance not provided 2025-01-31 criteria provided, single submitter clinical testing Identified in a proband from a Heritable Thoracic Aortic Aneurysms or Dissections (HTAD) cohort in the published literature (PMID: 32748548); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32748548)
Ambry Genetics RCV002313255 SCV000739505 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-07-05 criteria provided, single submitter clinical testing The p.P1337R variant (also known as c.4010C>G), located in coding exon 24 of the NOTCH1 gene, results from a C to G substitution at nucleotide position 4010. The proline at codon 1337 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in a hereditable thoracic aortic aneurysm cohort; however, clinical details were limited (Musfee FI et al. Mol Genet Genomic Med, 2020 10;8:e1406). 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000655253 SCV000777183 uncertain significance Adams-Oliver syndrome 5 2024-10-07 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1337 of the NOTCH1 protein (p.Pro1337Arg). This variant is not present in population databases (gnomAD no frequency). 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: 423102). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt NOTCH1 protein function with a negative predictive value of 80%. 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.
AiLife Diagnostics, AiLife Diagnostics RCV000481924 SCV002503111 uncertain significance not provided 2021-12-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000655253 SCV002553450 uncertain significance Adams-Oliver syndrome 5 2022-03-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002270582 SCV002553451 uncertain significance Aortic valve disease 1 2022-03-15 criteria provided, single submitter clinical testing

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