rs120074135
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000271.5(NPC1):c.2848G>A(p.Val950Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000271.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.2848G>A | p.Val950Met | missense_variant | Exon 19 of 25 | ENST00000269228.10 | NP_000262.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.2848G>A | p.Val950Met | missense_variant | Exon 19 of 25 | 1 | NM_000271.5 | ENSP00000269228.4 | ||
NPC1 | ENST00000591051.1 | c.1924G>A | p.Val642Met | missense_variant | Exon 12 of 18 | 2 | ENSP00000467636.1 | |||
NPC1 | ENST00000591075.1 | n.481G>A | non_coding_transcript_exon_variant | Exon 1 of 3 | 4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152224Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250896Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135562
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461596Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727058
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152224Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74372
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Pathogenic:8
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patient had late-onset NPC -
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 950 of the NPC1 protein (p.Val950Met). This variant is present in population databases (rs120074135, gnomAD 0.007%). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 11333381, 17003072, 26984608, 27900365). ClinVar contains an entry for this variant (Variation ID: 2971). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NPC1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NPC1 function (PMID: 28193631, 30923329, 31699992). This variant disrupts the p.Val950 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25236789, 26981555). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. The c.2848G>A (p.V950M) variant has been previously reported in multiple patients with adult-onset Niemann-Pick disease and variant biochemical phenotype [PMID 11333381, 16126423, 26984608, 27900365] -
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not provided Pathogenic:1
Reported previously in association with Niemann-Pick disease, type C (NPC) (Millat et al., 2001; Millat et al., 2005; Sevin et al. 2007; Garver et al. 2010). Two patients with NPC who were apparently homozygous for the V950M variant had adult onset of neurological symptoms (Millat et al., 2001; Sevin et al. 2007); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15465421, 26666848, 19744920, 16126423, 26984608, 11333381, 17003072, 27900365) -
NPC1-related disorder Pathogenic:1
The NPC1 c.2848G>A variant is predicted to result in the amino acid substitution p.Val950Met. This patient is heterozygous in the NPC1 gene for a sequence variant defined as c.2848G>A, which is predicted to result in the amino acid substitution p.Val950Met. This variant has been reported in the homozygous and compound heterozygous states in individuals with adult onset Niemann-Pick disease type C (Patient 22, Millat et al. 2001. PubMed ID: 11333381; Sévin et al. 2007. PubMed ID: 17003072; Dougherty et al. 2016. PubMed ID: 27900365; Sedel et al. 2016. PubMed ID: 26984608). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Taken together, this variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at