ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3493G>A (p.Val1165Met) (rs748862167)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000176359 SCV000228000 uncertain significance not provided 2014-08-14 criteria provided, single submitter clinical testing
Invitae RCV000704311 SCV000833255 likely pathogenic Niemann-Pick disease type C1 2019-06-03 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1165 of the NPC1 protein (p.Val1165Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs748862167, ExAC 0.002%). This variant has been observed on the opposite chromosome (in trans) from a likely pathogenic variant in an individual affected with Niemann-Pick C (PMID: 23430855). Additionally, it has been reported in multiple individuals affected with NPC disease both as a homozygous or heterozygous in combination with another NPC1 variant (PMID: 11349231, 17160617, 26666848, 25349751, 19744920). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 195723). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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