ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3557G>A (p.Arg1186His) (rs200444084)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000479463 SCV000339684 likely pathogenic not provided 2016-03-30 criteria provided, single submitter clinical testing
GeneDx RCV000479463 SCV000568739 pathogenic not provided 2017-02-24 criteria provided, single submitter clinical testing The R1186H variant in the NPC1 gene has been reported previously in association with Niemann-Pick disease type C (NPC) when present in the homozygous state or with another disease causing variant (Carstea et al., 1997; Sztolsztener et al., 2010; Jahnova et al., 2014). The R1186H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1186H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (A1187G, A1187V, E1189G, L1191F) have been reported in the Human Gene Mutation Database in association with NPC (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R1186H as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193399 SCV001362187 pathogenic Niemann-Pick disease, type C 2020-09-21 criteria provided, single submitter clinical testing Variant summary: NPC1 c.3557G>A (p.Arg1186His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 252814 control chromosomes. c.3557G>A has been widely reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C and subsequently cited by others (example, Reunert_2016, Carstea_1997, Imrie_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, at-least one study reported the identification of this variant in a homozygous affected individual with elevated oxysterol levels that are oxidation products of accumulated cholesterol in NP-C cells (Reunert_2016), and serve as a biomarker for the diagnosis of Niemann Pick type C disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic. Several submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169602 SCV001374807 pathogenic Niemann-Pick disease type C1 2020-10-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1186 of the NPC1 protein (p.Arg1186His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs200444084, ExAC 0.02%). This variant has been observed in several individuals affected with Niemann-Pick disease (PMID: 9211849, 22326530, 26666848, 28105569). ClinVar contains an entry for this variant (Variation ID: 189174). This variant has been reported to affect NPC1 protein function (PMID: 30923329). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000169602 SCV000221121 pathogenic Niemann-Pick disease type C1 2018-12-21 no assertion criteria provided clinical testing

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