rs369368181
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000271.5(NPC1):c.1628C>T(p.Pro543Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,770 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. P543S) 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.1628C>T | p.Pro543Leu | missense_variant | 10/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.1628C>T | p.Pro543Leu | missense_variant | 10/25 | 1 | NM_000271.5 | P1 | |
NPC1 | ENST00000591051.1 | c.835+3105C>T | intron_variant | 2 | |||||
NPC1 | ENST00000540608.5 | n.1542C>T | non_coding_transcript_exon_variant | 8/16 | 2 | ||||
NPC1 | ENST00000590301.1 | n.303C>T | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251218Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135770
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461598Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727122
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74338
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jun 14, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 543 of the NPC1 protein (p.Pro543Leu). This variant is present in population databases (rs369368181, gnomAD 0.01%). This missense change has been observed in individuals with Niemann-Pick Type C disease (PMID: 12955717, 16126423, 19744920, 22476655, 22676771). ClinVar contains an entry for this variant (Variation ID: 181455). 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. - |
Niemann-Pick disease, type C Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 05, 2024 | Variant summary: NPC1 c.1628C>T (p.Pro543Leu) 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 1.6e-05 in 251218 control chromosomes. c.1628C>T has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C (example, Chien_2013, Garver_2010, Heron_2012, Labrecque_2021, Millat_2005, Park_2003). 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. The following publications have been ascertained in the context of this evaluation (PMID: 22476655, 19744920, 22676771, 34799641, 16126423, 12955717). ClinVar contains an entry for this variant (Variation ID: 181455). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 14, 2017 | The p.Pro543Leu (NM_000271.4 c.1628C>T) variant in NPC1 has been reported in 1 h omozygous and 4 compound heterozygous individuals with Niemann-Pick disease type C (Millat 2005, Garver 2010, Heron 2012, and Chien 2013). This variant is absen t from ExAC but has been identified in 1/8,600 of European chromosomes by the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs3693681 81). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease type C in an autosomal recessive manner based upon its bial lelic occurrence in patients and low frequency in controls. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at