NM_000543.5(SMPD1):c.1716C>G (p.Phe572Leu) AND Sphingomyelin/cholesterol lipidosis

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 2, 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:: RCV003330487.1

Allele description [Variation Report for NM_000543.5(SMPD1):c.1716C>G (p.Phe572Leu)]

NM_000543.5(SMPD1):c.1716C>G (p.Phe572Leu)

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.1716C>G (p.Phe572Leu)

HGVS:

NC_000011.10:g.6394427C>G
NG_011780.1:g.9003C>G
NG_029615.1:g.29988G>C
NM_000543.5:c.1716C>GMANE SELECT
NM_001007593.3:c.1713C>G
NM_001318087.2:c.*209C>G
NM_001318088.2:c.795C>G
NM_001365135.2:c.1584C>G
NP_000534.3:p.Phe572Leu
NP_001007594.2:p.Phe571Leu
NP_001305017.1:p.Phe265Leu
NP_001352064.1:p.Phe528Leu
NC_000011.9:g.6415657C>G
NM_000543.4:c.1716C>G
NR_027400.3:n.1669C>G
NR_134502.2:n.1208C>G

Protein change:

F265L

Molecular consequence:

NM_001318087.2:c.*209C>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000543.5:c.1716C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001007593.3:c.1713C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001318088.2:c.795C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365135.2:c.1584C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_027400.3:n.1669C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134502.2:n.1208C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Sphingomyelin/cholesterol lipidosis
Synonyms:: Niemann-Pick disease
Identifiers:: MONDO: MONDO:0001982; MedGen: C0028064

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004039546	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Aug 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004039546

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Aug 2, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

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

Molecular genetic characterization of novel sphingomyelin phosphodiesterase 1 mutations causing niemann-pick disease.

Tóth B, Erdős M, Székely A, Ritli L, Bagossi P, Sümegi J, Maródi L.

JIMD Rep. 2012;3:125-9. doi: 10.1007/8904_2011_80. Epub 2011 Sep 27.

PubMed [citation]

PMID:: 23430884
PMCID:: PMC3509870

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004039546.1

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

Description

Variant summary: SMPD1 c.1716C>G (p.Phe572Leu) results in a non-conservative amino acid change to a well-conserved residue (HGMD) located in the Sphingomyelin phosphodiesterase, C-terminal domain (IPR045473) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251488 control chromosomes (gnomAD). c.1716C>G has been reported in the literature in an individual affected with Niemann-Pick Disease who was compound heterozygous with a likely pathogenic variant (Toth_2012). These data suggest the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant effect results in <30% of normal acid sphingomyelinase activity (Toth_2012). The following publication has been ascertained in the context of this evaluation (PMID: 23430884). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely 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: Apr 6, 2024

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