NM_000543.5(SMPD1):c.1117C>T (p.Pro373Ser) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 22, 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:: RCV003767346.1

Allele description [Variation Report for NM_000543.5(SMPD1):c.1117C>T (p.Pro373Ser)]

NM_000543.5(SMPD1):c.1117C>T (p.Pro373Ser)

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.1117C>T (p.Pro373Ser)

HGVS:

NC_000011.10:g.6393241C>T
NG_011780.1:g.7817C>T
NG_029615.1:g.31174G>A
NM_000543.5:c.1117C>TMANE SELECT
NM_001007593.3:c.1114C>T
NM_001318087.2:c.1117C>T
NM_001318088.2:c.196C>T
NM_001365135.2:c.1132-376C>T
NP_000534.3:p.Pro373Ser
NP_001007594.2:p.Pro372Ser
NP_001305016.1:p.Pro373Ser
NP_001305017.1:p.Pro66Ser
NC_000011.9:g.6414471C>T
NR_134502.2:n.589C>T

Protein change:

P372S

Links:

dbSNP: rs1342372980

NCBI 1000 Genomes Browser:

rs1342372980

Molecular consequence:

NM_001365135.2:c.1132-376C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000543.5:c.1117C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001007593.3:c.1114C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318087.2:c.1117C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318088.2:c.196C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_134502.2:n.589C>T - 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
SCV004569720	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 22, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22818240, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004569720

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 22, 2023)

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 (Asm) deficiency patients in The Netherlands and Belgium: disease spectrum and natural course in attenuated patients.

Hollak CE, de Sonnaville ES, Cassiman D, Linthorst GE, Groener JE, Morava E, Wevers RA, Mannens M, Aerts JM, Meersseman W, Akkerman E, Niezen-Koning KE, Mulder MF, Visser G, Wijburg FA, Lefeber D, Poorthuis BJ.

Mol Genet Metab. 2012 Nov;107(3):526-33. doi: 10.1016/j.ymgme.2012.06.015. Epub 2012 Jun 30.

PubMed [citation]

PMID:: 22818240

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 Invitae, SCV004569720.1

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

Description

This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 496822). This variant is also known as P371S. This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 22818240). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 373 of the SMPD1 protein (p.Pro373Ser). For these reasons, this variant has been classified as 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.

#	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: Apr 15, 2024

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