rs759826138
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000271.5(NPC1):c.2872C>T(p.Arg958Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,640 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R958R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000271.5 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.2872C>T | p.Arg958Ter | stop_gained | 19/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.2872C>T | p.Arg958Ter | stop_gained | 19/25 | 1 | NM_000271.5 | P1 | |
NPC1 | ENST00000591051.1 | c.1951C>T | p.Arg651Ter | stop_gained | 12/18 | 2 | |||
NPC1 | ENST00000591075.1 | n.505C>T | non_coding_transcript_exon_variant | 1/3 | 4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251158Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135714
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461640Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727094
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 12, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 07, 2023 | This sequence change creates a premature translational stop signal (p.Arg958*) in the NPC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPC1 are known to be pathogenic (PMID: 9211850). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 287837). This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease type C (PMID: 11349231, 23773996). This variant is present in population databases (rs759826138, gnomAD 0.003%). - |
Niemann-Pick disease, type C Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 20, 2021 | Variant summary: NPC1 c.2872C>T (p.Arg958X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251158 control chromosomes. c.2872C>T has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C (Sun_2001, Fancello_2009, Heron_2012, PerezMaturo_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication also reported experimental evidence evaluating an impact on protein function, and demonstrated impaired esterification of LDL-derived cholesterol in patient derived fibroblasts (Sun_2001). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 27, 2016 | - - |
Niemann-Pick disease, type C1, juvenile form Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | May 23, 2019 | This nonsense variant found in exon 19 of 25 is predicted to result in loss of normal protein function. This variant has been previously reported as a compound heterozygous change in patients with Niemann-Pick disease (PMID: 23773996). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.00039% (1/251158) and thus is presumed to be rare. This variant has been previously classified as Pathogenic by multiple clinical labs in the ClinVar database (Variation ID: 287837). Based on the available evidence, the c.2872C>T (p.Arg958Ter) variant is classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at