rs372445155
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000271.5(NPC1):c.1421C>T(p.Pro474Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,884 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P474A) 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.1421C>T | p.Pro474Leu | missense_variant | 9/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.1421C>T | p.Pro474Leu | missense_variant | 9/25 | 1 | NM_000271.5 | P1 | |
NPC1 | ENST00000591051.1 | c.704C>T | p.Pro235Leu | missense_variant | 4/18 | 2 | |||
NPC1 | ENST00000540608.5 | n.1335C>T | non_coding_transcript_exon_variant | 7/16 | 2 | ||||
NPC1 | ENST00000590301.1 | n.96C>T | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251462Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135896
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461714Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727182
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74322
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 474 of the NPC1 protein (p.Pro474Leu). This variant is present in population databases (rs372445155, gnomAD 0.007%). This missense change has been observed in individual(s) with Niemann-Pick type C (PMID: 12401890, 16086131, 16098014). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 374049). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 08, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12401890, 16086131, 34426522, 31743419, 33598405, 30119649, 35892469, 32138288) - |
Cataplexy;C0007758:Cerebellar ataxia;C0018681:Headache;C0264611:Speech apraxia;C0338656:Cognitive impairment;C1843921:Postural instability Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Oct 07, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at