ClinVar Miner

Submissions for variant NM_006432.5(NPC2):c.115G>A (p.Val39Met)

gnomAD frequency: 0.00001  dbSNP: rs80358261
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000009004 SCV004281705 uncertain significance Niemann-Pick disease, type C2 2023-10-22 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 39 of the NPC2 protein (p.Val39Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Niemann–Pick disease type C (PMID: 12447927). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8483). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect NPC2 function (PMID: 15937921). 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.
OMIM RCV000009004 SCV000029218 pathogenic Niemann-Pick disease, type C2 2002-12-01 no assertion criteria provided literature only
GeneReviews RCV000009004 SCV000041165 not provided Niemann-Pick disease, type C2 no assertion provided literature only
PreventionGenetics, part of Exact Sciences RCV003407307 SCV004114501 uncertain significance NPC2-related disorder 2024-01-30 no assertion criteria provided clinical testing The NPC2 c.115G>A variant is predicted to result in the amino acid substitution p.Val39Met. This variant was reported in the homozygous state in two sisters who presented in middle age with dementia and hallucinations (Klunemann et al. 2002. PubMed ID: 12447927). In functional studies, the p.Val39Met substitution was reported to result in functionally normal NPC2 protein (Chikh et al. 2005. PubMed ID: 15937921). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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