NM_000271.5(NPC1):c.423_424dup (p.Lys142fs) AND Niemann-Pick disease, type C

Clinical significance:Likely pathogenic (Last evaluated: Apr 11, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001193397.1

Allele description [Variation Report for NM_000271.5(NPC1):c.423_424dup (p.Lys142fs)]

NM_000271.5(NPC1):c.423_424dup (p.Lys142fs)

Gene:
NPC1:NPC intracellular cholesterol transporter 1 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
18q11.2
Genomic location:
Preferred name:
NM_000271.5(NPC1):c.423_424dup (p.Lys142fs)
HGVS:
  • NC_000018.10:g.23568862_23568863dup
  • NG_012795.1:g.22755_22756dup
  • NM_000271.5:c.423_424dupMANE SELECT
  • NP_000262.2:p.Lys142fs
  • NC_000018.9:g.21148825_21148826insTC
  • NC_000018.9:g.21148826_21148827dup
  • NM_000271.4:c.423_424dup
  • NM_000271.4:c.423_424dupGA
Protein change:
K142fs
Links:
dbSNP: rs773941375
NCBI 1000 Genomes Browser:
rs773941375
Molecular consequence:
  • NM_000271.5:c.423_424dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001362185Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Apr 11, 2019)
germlineclinical testing

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

Citation Link

Summary from all submissions

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

Citations

PubMed

High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets.

Wassif CA, Cross JL, Iben J, Sanchez-Pulido L, Cougnoux A, Platt FM, Ory DS, Ponting CP, Bailey-Wilson JE, Biesecker LG, Porter FD.

Genet Med. 2016 Jan;18(1):41-8. doi: 10.1038/gim.2015.25. Epub 2015 Mar 12.

PubMed [citation]
PMID:
25764212
PMCID:
PMC4486368

Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1.

Park WD, O'Brien JF, Lundquist PA, Kraft DL, Vockley CW, Karnes PS, Patterson MC, Snow K.

Hum Mutat. 2003 Oct;22(4):313-25.

PubMed [citation]
PMID:
12955717
See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362185.1

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

Description

Variant summary: NPC1 c.423_424dupGA (p.Lys142ArgfsX80) 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 (eg. c.2972_2973delAG (p.Gln991fsX15), c.3742_3745delCTCA (p.Leu1248fsX3)). The variant allele was found at a frequency of 1.1e-05 in 277192 control chromosomes (gnomAD) and has been reported in the literature in individuals affected with Niemann-Pick Disease Type C (Mazzacuva_2016, Park_2003). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Nov 27, 2021

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