NM_000271.5(NPC1):c.688_693del (p.Ser230_Val231del) AND Niemann-Pick disease type C1

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Sep 8, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000669390.3

Allele description [Variation Report for NM_000271.5(NPC1):c.688_693del (p.Ser230_Val231del)]

NM_000271.5(NPC1):c.688_693del (p.Ser230_Val231del)

Gene:
NPC1:NPC intracellular cholesterol transporter 1 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
18q11.2
Genomic location:
Preferred name:
NM_000271.5(NPC1):c.688_693del (p.Ser230_Val231del)
HGVS:
  • NC_000018.10:g.23560420_23560425del
  • NG_012795.1:g.31194_31199del
  • NM_000271.5:c.688_693delMANE SELECT
  • NP_000262.2:p.Ser230_Val231del
  • NC_000018.9:g.21140383_21140388del
  • NC_000018.9:g.21140384_21140389del
  • NM_000271.4:c.688_693del
  • NM_000271.4:c.688_693delTCTGTG
Links:
dbSNP: rs758687942
NCBI 1000 Genomes Browser:
rs758687942
Molecular consequence:
  • NM_000271.5:c.688_693del - inframe_deletion - [Sequence Ontology: SO:0001822]

Condition(s)

Name:
Niemann-Pick disease type C1 (NPC1)
Synonyms:
NIEMANN-PICK DISEASE WITHOUT SPHINGOMYELINASE DEFICIENCY; Niemann-Pick disease with cholesterol esterification block; Niemann-Pick disease, chronic neuronopathic form; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009757; MedGen: C3179455; Orphanet: 646; OMIM: 257220

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000794138Counsylcriteria provided, single submitter
Uncertain significance
(Sep 15, 2017)
unknownclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV001410264Invitaecriteria provided, single submitter
Likely pathogenic
(Sep 8, 2020)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1.

Sun X, Marks DL, Park WD, Wheatley CL, Puri V, O'Brien JF, Kraft DL, Lundquist PA, Patterson MC, Pagano RE, Snow K.

Am J Hum Genet. 2001 Jun;68(6):1361-72. Epub 2001 May 9.

PubMed [citation]
PMID:
11349231
PMCID:
PMC1226123

The National Niemann-Pick Type C1 Disease Database: correlation of lipid profiles, mutations, and biochemical phenotypes.

Garver WS, Jelinek D, Meaney FJ, Flynn J, Pettit KM, Shepherd G, Heidenreich RA, Vockley CM, Castro G, Francis GA.

J Lipid Res. 2010 Feb;51(2):406-15. doi: 10.1194/jlr.P000331. Epub 2009 Sep 9.

PubMed [citation]
PMID:
19744920
PMCID:
PMC2803243
See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000794138.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001410264.2

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

Description

This variant, c.688_693del, results in the deletion of 2 amino acid(s) of the NPC1 protein (p.Ser230_Val231del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758687942, ExAC 0.01%). This variant has been observed in individuals affected with NPC1-related conditions (PMID: 11349231, 19744920, 26666848). ClinVar contains an entry for this variant (Variation ID: 290134). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been 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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