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NM_000543.5(SMPD1):c.475T>C (p.Cys159Arg) AND Niemann-Pick disease, type B

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Apr 4, 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:
RCV001174779.12

Allele description [Variation Report for NM_000543.5(SMPD1):c.475T>C (p.Cys159Arg)]

NM_000543.5(SMPD1):c.475T>C (p.Cys159Arg)

Gene:
SMPD1:sphingomyelin phosphodiesterase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11p15.4
Genomic location:
Preferred name:
NM_000543.5(SMPD1):c.475T>C (p.Cys159Arg)
HGVS:
  • NC_000011.10:g.6391540T>C
  • NG_011780.1:g.6116T>C
  • NM_000543.5:c.475T>CMANE SELECT
  • NM_001007593.3:c.472T>C
  • NM_001318087.2:c.475T>C
  • NM_001318088.2:c.-487T>C
  • NM_001365135.2:c.475T>C
  • NP_000534.3:p.Cys159Arg
  • NP_000534.3:p.Cys159Arg
  • NP_001007594.2:p.Cys158Arg
  • NP_001305016.1:p.Cys159Arg
  • NP_001352064.1:p.Cys159Arg
  • NC_000011.9:g.6412770T>C
  • NM_000543.4(SMPD1):c.475T>C
  • NM_000543.4:c.475T>C
  • NR_027400.3:n.600T>C
Protein change:
C158R
Links:
dbSNP: rs727504166
NCBI 1000 Genomes Browser:
rs727504166
Molecular consequence:
  • NM_001318088.2:c.-487T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000543.5:c.475T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001007593.3:c.472T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318087.2:c.475T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365135.2:c.475T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_027400.3:n.600T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Niemann-Pick disease, type B
Identifiers:
MONDO: MONDO:0011871; MedGen: C0268243; Orphanet: 77293; OMIM: 607616

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001338109Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Likely pathogenic
(Apr 4, 2023) 		germlineclinical testing

PubMed (9)
[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

The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations.

Simonaro CM, Desnick RJ, McGovern MM, Wasserstein MP, Schuchman EH.

Am J Hum Genet. 2002 Dec;71(6):1413-9. Epub 2002 Oct 4.

PubMed [citation]
PMID:
12369017
PMCID:
PMC378582

SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants.

Zampieri S, Filocamo M, Pianta A, Lualdi S, Gort L, Coll MJ, Sinnott R, Geberhiwot T, Bembi B, Dardis A.

Hum Mutat. 2016 Feb;37(2):139-47. doi: 10.1002/humu.22923. Epub 2015 Dec 1. Review.

PubMed [citation]
PMID:
26499107
See all PubMed Citations (9)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338109.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

Variant summary: SMPD1 c.475T>C (p.Cys159Arg) results in a non-conservative amino acid change located in the Saposin B type domain (IPR008139) of the encoded protein sequence. This domain has been reported to have functional importance for ASM catalytic activity (Simonaro_2002). Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250578 control chromosomes (gnomAD). c.475T>C has been reported in the literature in individuals affected with Niemann-Pick disease type B and subsequently cited by others (e.g. McGovern_2004). These data indicate that the variant may be associated with disease. The variant has also been detected in individuals affected with Parkinsons's Disease, without strong evidence for causality (e.g. Robak_2017, Alcalay_2019). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of catalytic activity (10%-<30% of normal activity) in vitro (Ida_1993). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely 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: Oct 26, 2024