rs1555634422
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000271.5(NPC1):c.2072C>T(p.Pro691Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,884 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. P691Q) 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.2072C>T | p.Pro691Leu | missense_variant | 13/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.2072C>T | p.Pro691Leu | missense_variant | 13/25 | 1 | NM_000271.5 | P1 | |
NPC1 | ENST00000591051.1 | c.1151C>T | p.Pro384Leu | missense_variant | 6/18 | 2 | |||
NPC1 | ENST00000540608.5 | n.1986C>T | non_coding_transcript_exon_variant | 11/16 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727246
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 22, 2021 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals with Niemann-Pick disease type C (PMID: 25236789, 12955717, 27139891, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 552803). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 691 of the NPC1 protein (p.Pro691Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 14, 2023 | 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: 25236789, 27139891, 32248828, 12955717, 27535533, 33624863) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at