ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.6521A>G (p.Lys2174Arg) (rs761602495)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000247419 SCV000319614 uncertain significance Cardiovascular phenotype 2017-12-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Fulgent Genetics,Fulgent Genetics RCV000766054 SCV000897510 uncertain significance Aortic valve disorder; Adams-Oliver syndrome 5 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000493215 SCV000582567 uncertain significance not provided 2017-05-11 criteria provided, single submitter clinical testing The K2174R variant of uncertain significance in the NOTCH1 gene has been previously reported in an untreated patient diagnosed with chronic lymphocytic leukemia, although no information related to the individual's cardiac history was provided, and it is unclear whether the variant was germline or somatic (Jeromin et al., 2014). K2174R is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The K2174R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Moreover, this substitution occurs at a position where amino acids with similar properties to lysine are tolerated across species, and R2174 is the wild-type residue in multiple species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Lastly, no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causing variants.
Invitae RCV000692256 SCV000820070 uncertain significance Adams-Oliver syndrome 5 2018-05-15 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 2174 of the NOTCH1 protein (p.Lys2174Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs761602495, ExAC 0.006%). This variant has not been reported in the literature in individuals with NOTCH1-related disease. ClinVar contains an entry for this variant (Variation ID: 264003). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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