rs200444084
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000271.5(NPC1):c.3557G>A(p.Arg1186His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1186C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000271.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.3557G>A | p.Arg1186His | missense_variant | 23/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.3557G>A | p.Arg1186His | missense_variant | 23/25 | 1 | NM_000271.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152242Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251122Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135754
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461622Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9AN XY: 727120
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152360Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74498
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 24, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Dec 21, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 25, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NPC1 function (PMID: 30923329). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPC1 protein function. ClinVar contains an entry for this variant (Variation ID: 189174). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 9211849, 22326530, 26666848, 28105569). This variant is present in population databases (rs200444084, gnomAD 0.008%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1186 of the NPC1 protein (p.Arg1186His). - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 24, 2017 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 30, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 02, 2022 | PP3, PM2, PM3_very_strong, PM5, PS3, PS4 - |
Niemann-Pick disease, type C Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 21, 2020 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at