NM_000543.5(SMPD1):c.1493G>T (p.Arg498Leu) AND Inborn genetic diseases

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 29, 2021
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:: RCV004018542.1

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:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004954300	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jun 29, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 2023926, 12369017, 15221801, 18815062, 29995201 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004954300

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jun 29, 2021)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

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

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV004954300.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The c.1493G>T (p.R498L) alteration is located in exon 6 (coding exon 6) of the SMPD1 gene. This alteration results from a G to T substitution at nucleotide position 1493, causing the arginine (R) at amino acid position 498 to be replaced by a leucine (L). Based on data from the Genome Aggregation Database (gnomAD) database, the SMPD1 c.1493G>T alteration was observed in 0.01% (36/282454) of total alleles studied, with a frequency of 0.28% (29/10346) in the Ashkenazi Jewish subpopulation. This mutation (also referred to as p.R496L) has been reported in the homozygous and compound heterozygous states in patients with SMPD1-related Niemann-Pick disease and is a common mutation in the Ashkenazi Jewish population (Levran, 1991; Ricci, 2004; Cox, 2018). Other alterations at this amino acid position have also been reported in affected patients (Simonaro, 2002; Ricci, 2004). Functional studies demonstrated reduced enzymatic activity in patient fibroblasts and transgenic mice with this mutation (Jones, 2008). The p.R498L alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 17, 2024

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