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NM_000271.5(NPC1):c.410C>T (p.Thr137Met) AND Niemann-Pick disease, type C

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 18, 2023
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:
RCV003226316.1

Allele description [Variation Report for NM_000271.5(NPC1):c.410C>T (p.Thr137Met)]

NM_000271.5(NPC1):c.410C>T (p.Thr137Met)

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.410C>T (p.Thr137Met)
HGVS:
  • NC_000018.10:g.23568876G>A
  • NG_012795.1:g.22742C>T
  • NM_000271.5:c.410C>TMANE SELECT
  • NP_000262.2:p.Thr137Met
  • NC_000018.9:g.21148840G>A
  • NM_000271.4:c.410C>T
Protein change:
T137M
Links:
dbSNP: rs372947142
NCBI 1000 Genomes Browser:
rs372947142
Molecular consequence:
  • NM_000271.5:c.410C>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
SCV003922603Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Mar 18, 2023) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

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

Citations

PubMed

Purified NPC1 protein: II. Localization of sterol binding to a 240-amino acid soluble luminal loop.

Infante RE, Radhakrishnan A, Abi-Mosleh L, Kinch LN, Wang ML, Grishin NV, Goldstein JL, Brown MS.

J Biol Chem. 2008 Jan 11;283(2):1064-75. Epub 2007 Nov 6.

PubMed [citation]
PMID:
17989072

Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia.

Akizu N, Shembesh NM, Ben-Omran T, Bastaki L, Al-Tawari A, Zaki MS, Koul R, Spencer E, Rosti RO, Scott E, Nickerson E, Gabriel S, da Gente G, Li J, Deardorff MA, Conlin LK, Horton MA, Zackai EH, Sherr EH, Gleeson JG.

Am J Hum Genet. 2013 Mar 7;92(3):392-400. doi: 10.1016/j.ajhg.2013.02.004. Epub 2013 Feb 28.

PubMed [citation]
PMID:
23453666
PMCID:
PMC3591854
See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003922603.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: NPC1 c.410C>T (p.Thr137Met) results in a non-conservative amino acid change located in the Niemann-Pick C1, N-terminal domain (IPR032190) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251402 control chromosomes. c.410C>T has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C (example, PMID: 27378690, 29429782, 23453666). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported although one study reported normal binding to both 25-Hydroxycholesterol and Cholesterol (PMID: 17989072). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. 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: Sep 29, 2024