NM_000543.5(SMPD1):c.839A>C (p.Asp280Ala) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 2, 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:: RCV001390955.8

Allele description [Variation Report for NM_000543.5(SMPD1):c.839A>C (p.Asp280Ala)]

NM_000543.5(SMPD1):c.839A>C (p.Asp280Ala)

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.839A>C (p.Asp280Ala)

HGVS:

NC_000011.10:g.6391904A>C
NG_011780.1:g.6480A>C
NM_000543.5:c.839A>CMANE SELECT
NM_001007593.3:c.836A>C
NM_001318087.2:c.839A>C
NM_001318088.2:c.-123A>C
NM_001365135.2:c.839A>C
NP_000534.3:p.Asp280Ala
NP_001007594.2:p.Asp279Ala
NP_001305016.1:p.Asp280Ala
NP_001352064.1:p.Asp280Ala
NC_000011.9:g.6413134A>C
NR_027400.3:n.964A>C

Protein change:

D279A

Links:

dbSNP: rs1847935299

NCBI 1000 Genomes Browser:

rs1847935299

Molecular consequence:

NM_001318088.2:c.-123A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000543.5:c.839A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001007593.3:c.836A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318087.2:c.839A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001365135.2:c.839A>C - missense variant - [Sequence Ontology: SO:0001583]
NR_027400.3:n.964A>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
SCV001592862	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 2, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15877209, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001592862

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 2, 2024)

germline

clinical testing

PubMed (2)
[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

Acid sphingomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty-five Czech and Slovak patients. A multi-approach study.

Pavlů-Pereira H, Asfaw B, Poupctová H, Ledvinová J, Sikora J, Vanier MT, Sandhoff K, Zeman J, Novotná Z, Chudoba D, Elleder M.

J Inherit Metab Dis. 2005;28(2):203-27.

PubMed [citation]

PMID:: 15877209

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001592862.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 280 of the SMPD1 protein (p.Asp280Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 15877209). It has also been observed to segregate with disease in related individuals. This variant is also known as D278A. ClinVar contains an entry for this variant (Variation ID: 1076908). 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: 15877209). For these reasons, this variant has been 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: May 16, 2025

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