NM_000543.5(SMPD1):c.1297T>C (p.Cys433Arg) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 5, 2022
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:: RCV002549241.3

Allele description [Variation Report for NM_000543.5(SMPD1):c.1297T>C (p.Cys433Arg)]

NM_000543.5(SMPD1):c.1297T>C (p.Cys433Arg)

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.1297T>C (p.Cys433Arg)

HGVS:

NC_000011.10:g.6393650T>C
NG_011780.1:g.8226T>C
NG_029615.1:g.30765A>G
NM_000543.5:c.1297T>CMANE SELECT
NM_001007593.3:c.1294T>C
NM_001318087.2:c.1297T>C
NM_001318088.2:c.376T>C
NM_001365135.2:c.1165T>C
NP_000534.3:p.Cys433Arg
NP_001007594.2:p.Cys432Arg
NP_001305016.1:p.Cys433Arg
NP_001305017.1:p.Cys126Arg
NP_001352064.1:p.Cys389Arg
NC_000011.9:g.6414880T>C
NR_027400.3:n.1250T>C
NR_134502.2:n.769T>C

Protein change:

C126R

Links:

dbSNP: rs779528546

NCBI 1000 Genomes Browser:

rs779528546

Molecular consequence:

NM_000543.5:c.1297T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001007593.3:c.1294T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318087.2:c.1297T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318088.2:c.376T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001365135.2:c.1165T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_027400.3:n.1250T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134502.2:n.769T>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

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003439785	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Apr 5, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12369017, 27338287, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003439785

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Apr 5, 2022)

germline

clinical testing

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

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

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

Spectrum of SMPD1 mutations in Asian-Indian patients with acid sphingomyelinase (ASM)-deficient Niemann-Pick disease.

Ranganath P, Matta D, Bhavani GS, Wangnekar S, Jain JM, Verma IC, Kabra M, Puri RD, Danda S, Gupta N, Girisha KM, Sankar VH, Patil SJ, Ramadevi AR, Bhat M, Gowrishankar K, Mandal K, Aggarwal S, Tamhankar PM, Tilak P, Phadke SR, Dalal A.

Am J Med Genet A. 2016 Oct;170(10):2719-30. doi: 10.1002/ajmg.a.37817. Epub 2016 Jun 24.

PubMed [citation]

PMID:: 27338287

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003439785.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant is present in population databases (rs779528546, gnomAD 0.0009%). 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. 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. ClinVar contains an entry for this variant (Variation ID: 813420). This variant is also known as C431R. This missense change has been observed in individual(s) with SMPD1-related conditions (PMID: 12369017, 27338287). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 433 of the SMPD1 protein (p.Cys433Arg).

#	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: Sep 29, 2024

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