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NM_000271.5(NPC1):c.2974G>T (p.Gly992Trp) AND Niemann-Pick disease, type C

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Oct 4, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV004799729.1

Allele description [Variation Report for NM_000271.5(NPC1):c.2974G>T (p.Gly992Trp)]

NM_000271.5(NPC1):c.2974G>T (p.Gly992Trp)

Gene:
NPC1:NPC intracellular cholesterol transporter 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
18q11.2
Genomic location:
Preferred name:
NM_000271.5(NPC1):c.2974G>T (p.Gly992Trp)
HGVS:
  • NC_000018.10:g.23538609C>A
  • NG_012795.1:g.53009G>T
  • NM_000271.5:c.2974G>TMANE SELECT
  • NP_000262.2:p.Gly992Trp
  • NC_000018.9:g.21118573C>A
  • NM_000271.3:c.2974G>T
  • NM_000271.4:c.2974G>T
  • O15118:p.Gly992Trp
Protein change:
G992W; GLY992TRP
Links:
UniProtKB: O15118#VAR_008833; OMIM: 607623.0004; dbSNP: rs80358254
NCBI 1000 Genomes Browser:
rs80358254
Molecular consequence:
  • NM_000271.5:c.2974G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Niemann-Pick disease, type C (NPC)
Identifiers:
MONDO: MONDO:0018982; MedGen: C0220756

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005423408Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Oct 4, 2024) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

The Nova Scotia (type D) form of Niemann-Pick disease is caused by a G3097-->T transversion in NPC1.

Greer WL, Riddell DC, Gillan TL, Girouard GS, Sparrow SM, Byers DM, Dobson MJ, Neumann PE.

Am J Hum Genet. 1998 Jul;63(1):52-4.

PubMed [citation]
PMID:
9634529
PMCID:
PMC1377252

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005423408.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

Variant summary: NPC1 c.2974G>T (p.Gly992Trp) 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 2e-05 in 251484 control chromosomes (gnomAD). c.2974G>T has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C (e.g. Greer_1998). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.2974G>C, p.Gly992Arg), supporting the critical relevance of codon 992 to NPC1 protein function. The following publication has been ascertained in the context of this evaluation (PMID: 9634529). ClinVar contains an entry for this variant (Variation ID: 2960). Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 14, 2024