rs1555632003
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000271.5(NPC1):c.3500T>G(p.Phe1167Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F1167L) 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 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.3500T>G | p.Phe1167Cys | missense_variant | 23/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.3500T>G | p.Phe1167Cys | missense_variant | 23/25 | 1 | NM_000271.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 04, 2022 | For these reasons, this variant has been classified as Pathogenic. 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: 557024). This missense change has been observed in individual(s) with Niemann-Pick type C (PMID: 23433426, 25149939). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1167 of the NPC1 protein (p.Phe1167Cys). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 02, 2018 | - - |
Niemann-Pick disease, type C Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 27, 2023 | Variant summary: NPC1 c.3500T>G (p.Phe1167Cys) 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 was absent in 251048 control chromosomes. c.3500T>G has been reported in the literature in individuals affected with Niemann-Pick Disease Type C (Mazzacuva_2016, Stampfer_2013, Tsao_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other variants resulting in p.F1167L have been associated with Niemann-Pick disease in HGMD. The following publications have been ascertained in the context of this evaluation (PMID: 27139891, 23433426, 25149939).Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at