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NM_000543.5(SMPD1):c.1493G>T (p.Arg498Leu) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 24, 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:
RCV000526587.18

Allele description [Variation Report for NM_000543.5(SMPD1):c.1493G>T (p.Arg498Leu)]

NM_000543.5(SMPD1):c.1493G>T (p.Arg498Leu)

Genes:
APBB1:amyloid beta precursor protein binding family B member 1 [Gene - OMIM - HGNC]
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.1493G>T (p.Arg498Leu)
Other names:
R496L
HGVS:
  • NC_000011.10:g.6394204G>T
  • NG_011780.1:g.8780G>T
  • NG_029615.1:g.30211C>A
  • NM_000543.4(SMPD1):c.1493G>T
  • NM_000543.5:c.1493G>TMANE SELECT
  • NM_001007593.3:c.1490G>T
  • NM_001318087.2:c.1513G>T
  • NM_001318088.2:c.572G>T
  • NM_001365135.2:c.1361G>T
  • NP_000534.3:p.Arg498Leu
  • NP_000534.3:p.Arg498Leu
  • NP_001007594.2:p.Arg497Leu
  • NP_001305016.1:p.Val505Leu
  • NP_001305017.1:p.Arg191Leu
  • NP_001352064.1:p.Arg454Leu
  • NC_000011.9:g.6415434G>T
  • NM_000543.3:c.1493G>T
  • NM_000543.4(SMPD1):c.1493G>T
  • NM_000543.4:c.1493G>T
  • NR_027400.3:n.1446G>T
  • NR_134502.2:n.985G>T
  • c.1493G>T (p.Arg498Leu)
  • p.Arg496Leu
Protein change:
R191L; ARG496LEU
Links:
OMIM: 607608.0001; dbSNP: rs120074117
NCBI 1000 Genomes Browser:
rs120074117
Molecular consequence:
  • NM_000543.5:c.1493G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001007593.3:c.1490G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318087.2:c.1513G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318088.2:c.572G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365135.2:c.1361G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_027400.3:n.1446G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_134502.2:n.985G>T - 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
Name:
Niemann-Pick disease, type A
Synonyms:
SPHINGOMYELIN LIPIDOSIS; SPHINGOMYELINASE DEFICIENCY
Identifiers:
MONDO: MONDO:0009756; MedGen: C0268242; Orphanet: 77292; OMIM: 257200

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000631412Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 24, 2024) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Niemann-Pick type B disease. Identification of a single codon deletion in the acid sphingomyelinase gene and genotype/phenotype correlations in type A and B patients.

Levran O, Desnick RJ, Schuchman EH.

J Clin Invest. 1991 Sep;88(3):806-10.

PubMed [citation]
PMID:
1885770
PMCID:
PMC295465

Niemann-Pick disease: a frequent missense mutation in the acid sphingomyelinase gene of Ashkenazi Jewish type A and B patients.

Levran O, Desnick RJ, Schuchman EH.

Proc Natl Acad Sci U S A. 1991 May 1;88(9):3748-52.

PubMed [citation]
PMID:
2023926
PMCID:
PMC51530
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000631412.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 498 of the SMPD1 protein (p.Arg498Leu). This variant is present in population databases (rs120074117, gnomAD 0.3%). This missense change has been observed in individual(s) with Niemann-Pick disease types A and B (PMID: 1391960, 1885770, 2023926). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 1391960, 1885770, 2023926). This variant is also known as R496L. ClinVar contains an entry for this variant (Variation ID: 2980). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMPD1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 1391960, 18815062). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 26, 2024