ClinVar Miner

Submissions for variant NM_017617.5(NOTCH1):c.244G>A (p.Val82Met) (rs571831870)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494580 SCV000582027 uncertain significance not provided 2017-05-02 criteria provided, single submitter clinical testing The V82M variant of uncertain significance in the NOTCH1 gene has not been published as pathogenic or been reported as benign to our knowledge. V82M 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 V82M 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 that is not conserved, where M82 is the wild-type residue in at least two species. In silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae RCV000701769 SCV000830585 uncertain significance Adams-Oliver syndrome 5 2018-05-14 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 82 of the NOTCH1 protein (p.Val82Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs571831870, ExAC 0.02%). This variant has not been reported in the literature in individuals with NOTCH1-related disease. ClinVar contains an entry for this variant (Variation ID: 429449). 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 methionine 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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