18-23539826-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000269228.10(NPC1):c.2780C>T(p.Ala927Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,846 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A927G) has been classified as Pathogenic.
Frequency
Consequence
ENST00000269228.10 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.2780C>T | p.Ala927Val | missense_variant | 18/25 | ENST00000269228.10 | NP_000262.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.2780C>T | p.Ala927Val | missense_variant | 18/25 | 1 | NM_000271.5 | ENSP00000269228.4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251354Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135888
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461846Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5AN XY: 727228
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2023 | 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: 552715). This missense change has been observed in individual(s) with Niemann-Pick type C (PMID: 11545687, 27366019, 27549128). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs753768576, gnomAD 0.01%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 927 of the NPC1 protein (p.Ala927Val). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 03, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 15, 2022 | - - |
Niemann-Pick disease, type C Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 16, 2024 | Variant summary: NPC1 c.2780C>T (p.Ala927Val) 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 2.4e-05 in 251354 control chromosomes. c.2780C>T has been reported in the literature as homozygous or in compound heterozygous state with a pathogenic variant in multiple individuals affected with Niemann-Pick Disease Type C (Meiner_2001, Lee_2016, Cervera-Gaviria_2016, Hwang_2023). This variant has also been shown to segregate with disease in at least two families (Meiner_2001, Lee_2016). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 27549128, 32222928, 36636588, 27366019, 11545687). ClinVar contains an entry for this variant (Variation ID: 552715). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 11, 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: 9400363, 34535129, 11545687, 27549128, 27366019, 32222928, 33767182) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at