ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.5492T>C (p.Leu1831Pro)

gnomAD frequency: 0.00001  dbSNP: rs1085307869
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489091 SCV000577538 uncertain significance not provided 2024-05-01 criteria provided, single submitter clinical testing 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; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV000655224 SCV000777154 uncertain significance Adams-Oliver syndrome 5 2025-01-23 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1831 of the NOTCH1 protein (p.Leu1831Pro). 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: 426954). 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.
Genome-Nilou Lab RCV000655224 SCV002553342 uncertain significance Adams-Oliver syndrome 5 2022-03-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002270586 SCV002553343 uncertain significance Aortic valve disease 1 2022-03-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV002350089 SCV002650065 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2024-07-16 criteria provided, single submitter clinical testing The p.L1831P variant (also known as c.5492T>C), located in coding exon 30 of the NOTCH1 gene, results from a T to C substitution at nucleotide position 5492. The leucine at codon 1831 is replaced by proline, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000489091 SCV004563418 uncertain significance not provided 2023-10-03 criteria provided, single submitter clinical testing The NOTCH1 c.5492T>C; p.Leu1831Pro variant (rs1085307869), to our knowledge, is not reported in the medical literature in NOTCH1-related conditions but is reported in ClinVar (Variation ID: 426954). This variant is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.563). Due to limited information, the clinical significance of this variant is uncertain at this time.

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