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NM_000543.5(SMPD1):c.1493G>T (p.Arg498Leu) AND SMPD1-related disorder

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 3, 2024
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV004742209.1

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:
SMPD1-related disorder
Synonyms:
SMPD1-related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005356426PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Pathogenic
(Jul 3, 2024) 		germlineclinical testing

Help

Summary from all submissions

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

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV005356426.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The SMPD1 c.1493G>T variant is predicted to result in the amino acid substitution p.Arg498Leu. This variant has been reported in individuals with Niemann-Pick disease type A (referred to as R496L, Levran et al. 1991. PubMed ID: 2023926). This variant is reported to be one of three variants that account for approximately 90% of pathogenic alleles in individuals of Ashkenazi Jewish ancestry (Wasserstein and Schuchman et al. 2021. PubMed ID: 20301544). In vitro, in situ, and in vivo experimental studies indicate that this variant almost completely abolishes the enzyme activity of the SMPD1 protein (referred to as R496L, Jones et al 2008. PubMed ID: 18815062). This variant is reported in 0.28% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, but is not observed in individuals of non-Ashkenazi Jewish ancestry. Alternate nucleotide changes affecting the same amino acid (p.Arg498Cys, p.Arg498His, and p.Arg498Pro) have been reported in individuals with Niemann-Pick disease type A (Simonaro et al. 2002. PubMed ID: 12369017; Ricci et al. 2004. PubMed ID: 15221801; Hu et al. 2021. PubMed ID: 33675270). The c.1493G>T (p.Arg498Leu) variant is interpreted as pathogenic.

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

Last Updated: Jan 13, 2025