ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.2801G>A (p.Arg934Gln) (rs786204714)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169530 SCV000221009 likely pathogenic Niemann-Pick disease type C1 2015-01-06 criteria provided, single submitter literature only
Invitae RCV000169530 SCV000963974 likely pathogenic Niemann-Pick disease type C1 2019-06-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 934 of the NPC1 protein (p.Arg934Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Niemann-Pick disease (PMID: 10521290, 16126423, 17160617, 25236789). ClinVar contains an entry for this variant (Variation ID: 189117). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197209 SCV001367846 pathogenic Hypomimic face; Parkinsonism; Rigidity 2019-02-18 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2. This variant was detected in heterozygous state.

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