NM_000543.5(SMPD1):c.592G>C (p.Ala198Pro) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 5, 2023
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:: RCV001852412.14

Allele description [Variation Report for NM_000543.5(SMPD1):c.592G>C (p.Ala198Pro)]

NM_000543.5(SMPD1):c.592G>C (p.Ala198Pro)

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.592G>C (p.Ala198Pro)

HGVS:

NC_000011.10:g.6391657G>C
NG_011780.1:g.6233G>C
NM_000543.4(SMPD1):c.592G>C
NM_000543.5:c.592G>CMANE SELECT
NM_001007593.3:c.589G>C
NM_001318087.2:c.592G>C
NM_001318088.2:c.-370G>C
NM_001365135.2:c.592G>C
NP_000534.3:p.Ala198Pro
NP_000534.3:p.Ala198Pro
NP_001007594.2:p.Ala197Pro
NP_001305016.1:p.Ala198Pro
NP_001352064.1:p.Ala198Pro
NC_000011.9:g.6412887G>C
NM_000543.3:c.592G>C
NM_000543.4(SMPD1):c.592G>C
NM_000543.4:c.592G>C
NM_000543.5:c.592G>C
NR_027400.3:n.717G>C
p.Ala196Pro

Protein change:

A197P

Links:

dbSNP: rs797044798

NCBI 1000 Genomes Browser:

rs797044798

Molecular consequence:

NM_001318088.2:c.-370G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000543.5:c.592G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001007593.3:c.589G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318087.2:c.592G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001365135.2:c.592G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_027400.3:n.717G>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
SCV002254408	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 5, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12369017, 15234149, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002254408

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 5, 2023)

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

Ocular manifestations of Niemann-Pick disease type B.

McGovern MM, Wasserstein MP, Aron A, Desnick RJ, Schuchman EH, Brodie SE.

Ophthalmology. 2004 Jul;111(7):1424-7.

PubMed [citation]

PMID:: 15234149

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002254408.3

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 198 of the SMPD1 protein (p.Ala198Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with acid sphingomyelinase deficiency (PMID: 12369017, 15234149; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203425). 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%. 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: Oct 8, 2024

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