ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3183A>G (p.Ile1061Met)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001056282 SCV001220717 uncertain significance Niemann-Pick disease type C1 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 1061 of the NPC1 protein (p.Ile1061Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with clinical features of Niemann-Pick type C (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Ile1061 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10521297, 16126423, 25149939, 20521171). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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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