ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.6284G>T (p.Arg2095Leu)

dbSNP: rs756874994
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002315092 SCV000739433 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2016-07-14 criteria provided, single submitter clinical testing The p.R2095L variant (also known as c.6284G>T), located in coding exon 34 of the NOTCH1 gene, results from a G to T substitution at nucleotide position 6284. The arginine at codon 2095 is replaced by leucine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6469 samples (12938 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV001756010 SCV001986576 uncertain significance not provided 2025-03-18 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
Genome-Nilou Lab RCV002270887 SCV002553309 uncertain significance Adams-Oliver syndrome 5 2022-03-15 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002270886 SCV002553310 uncertain significance Aortic valve disease 1 2022-03-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002270887 SCV003520531 uncertain significance Adams-Oliver syndrome 5 2023-02-27 criteria provided, single submitter clinical testing Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOTCH1 protein function. ClinVar contains an entry for this variant (Variation ID: 520047). This variant has not been reported in the literature in individuals affected with NOTCH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 2095 of the NOTCH1 protein (p.Arg2095Leu). 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.

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