ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.2849T>G (p.Val950Gly) (rs1057517978)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414206 SCV000491261 likely pathogenic not provided 2016-01-29 criteria provided, single submitter clinical testing The V950G variant in the NPC1 gene has been reported previously as a pathogenic variant in a male Czech patient with a juvenile form of Niemann-Pick disease type C; V950G was observed in the heterozygous state along with a second pathogenic variant, P1007A, with unknown phase (Jahnova et al., 2014). The V950G variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V950G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and this substitution in fact occurs at a position where amino acids with similar properties to Valine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in the same (V950M) and nearby (D945N, D948Y, D948H, D948N, and S954L) residues have been reported in the Human Gene Mutation Database in association with Nieman-Pick disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. The V950G variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Illumina Clinical Services Laboratory,Illumina RCV000779241 SCV000915797 uncertain significance Niemann-Pick disease type C1 2018-03-14 criteria provided, single submitter clinical testing The NPC1 c.2849T>G (p.Val950Gly) variant has been reported in two studies and is found in a compound heterozygous state with a second missense variant in two individuals with known or suspected Neimann-Pick disease type C, including one in whom the phase was not confirmed (Jahnova et al. 2014; Reunert et al. 2016). Control data are unavailable for this variant. The p.Val950Gly variant is reported at a frequency of 0.000018 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. The evidence for this variant is limited. The p.Val950Gly variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Niemann-Pick disease type C. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl RCV000779241 SCV001132261 uncertain significance Niemann-Pick disease type C1 2016-05-04 no assertion criteria provided clinical testing

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