NM_000543.5(SMPD1):c.1718G>C (p.Trp573Ser) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 8, 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:: RCV002550507.2

Allele description [Variation Report for NM_000543.5(SMPD1):c.1718G>C (p.Trp573Ser)]

NM_000543.5(SMPD1):c.1718G>C (p.Trp573Ser)

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.1718G>C (p.Trp573Ser)

HGVS:

NC_000011.10:g.6394429G>C
NG_011780.1:g.9005G>C
NG_029615.1:g.29986C>G
NM_000543.5:c.1718G>CMANE SELECT
NM_001007593.3:c.1715G>C
NM_001318087.2:c.*211G>C
NM_001318088.2:c.797G>C
NM_001365135.2:c.1586G>C
NP_000534.3:p.Trp573Ser
NP_001007594.2:p.Trp572Ser
NP_001305017.1:p.Trp266Ser
NP_001352064.1:p.Trp529Ser
NC_000011.9:g.6415659G>C
NM_001365135.2:c.1586G>C
NR_027400.3:n.1671G>C
NR_134502.2:n.1210G>C

Protein change:

W266S

Links:

dbSNP: rs2134024060

NCBI 1000 Genomes Browser:

rs2134024060

Molecular consequence:

NM_001318087.2:c.*211G>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000543.5:c.1718G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001007593.3:c.1715G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318088.2:c.797G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001365135.2:c.1586G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_027400.3:n.1671G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134502.2:n.1210G>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
SCV002954024	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 8, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32292456, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002954024

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 8, 2022)

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

Mutational spectrum of SMPD1 gene in Pakistani Niemann-Pick disease patients.

Cheema HA, Rasool IG, Anjum MN, Zahoor MY.

Pak J Med Sci. 2020 Mar-Apr;36(3):479-484. doi: 10.12669/pjms.36.3.467.

PubMed [citation]

PMID:: 32292456
PMCID:: PMC7150380

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, SCV002954024.1

#	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 tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 573 of the SMPD1 protein (p.Trp573Ser). 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: 32292456). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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