NM_000543.5(SMPD1):c.1280A>T (p.His427Leu) AND multiple conditions

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 19, 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:: RCV001852206.3

Allele description

NM_000543.5(SMPD1):c.1280A>T (p.His427Leu)

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.1280A>T (p.His427Leu)

HGVS:

NC_000011.10:g.6393633A>T
NG_011780.1:g.8209A>T
NG_029615.1:g.30782T>A
NM_000543.5:c.1280A>TMANE SELECT
NM_001007593.3:c.1277A>T
NM_001318087.2:c.1280A>T
NM_001318088.2:c.359A>T
NM_001365135.2:c.1148A>T
NP_000534.3:p.His427Leu
NP_001007594.2:p.His426Leu
NP_001305016.1:p.His427Leu
NP_001305017.1:p.His120Leu
NP_001352064.1:p.His383Leu
NC_000011.9:g.6414863A>T
NR_027400.3:n.1233A>T
NR_134502.2:n.752A>T

Protein change:

H120L

Links:

dbSNP: rs794727629

NCBI 1000 Genomes Browser:

rs794727629

Molecular consequence:

NM_000543.5:c.1280A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001007593.3:c.1277A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318087.2:c.1280A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318088.2:c.359A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001365135.2:c.1148A>T - missense variant - [Sequence Ontology: SO:0001583]
NR_027400.3:n.1233A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134502.2:n.752A>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
SCV002287363	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 19, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20386867, 25144372, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002287363

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 19, 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

Identification and characterization of eight novel SMPD1 mutations causing types A and B Niemann-Pick disease.

Desnick JP, Kim J, He X, Wasserstein MP, Simonaro CM, Schuchman EH.

Mol Med. 2010 Jul-Aug;16(7-8):316-21. doi: 10.2119/molmed.2010.00017. Epub 2010 Apr 6.

PubMed [citation]

PMID:: 20386867
PMCID:: PMC2896470

Identification and biochemical characterization of an acid sphingomyelinase-like protein from the bacterial plant pathogen Ralstonia solanacearum that hydrolyzes ATP to AMP but not sphingomyelin to ceramide.

Airola MV, Tumolo JM, Snider J, Hannun YA.

PLoS One. 2014;9(8):e105830. doi: 10.1371/journal.pone.0105830.

PubMed [citation]

PMID:: 25144372
PMCID:: PMC4140839

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV002287363.3

#	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 histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 427 of the SMPD1 protein (p.His427Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMPD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 197160). 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%. This variant disrupts the p.His427 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20386867, 25144372). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been 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: Mar 5, 2024

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