NM_000543.5(SMPD1):c.1458T>G (p.Ser486Arg) AND multiple conditions

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 21, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000819539.8

Allele description [Variation Report for NM_000543.5(SMPD1):c.1458T>G (p.Ser486Arg)]

NM_000543.5(SMPD1):c.1458T>G (p.Ser486Arg)

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.1458T>G (p.Ser486Arg)

HGVS:

NC_000011.10:g.6394013T>G
NG_011780.1:g.8589T>G
NG_029615.1:g.30402A>C
NM_000543.5:c.1458T>GMANE SELECT
NM_001007593.3:c.1455T>G
NM_001318087.2:c.1458T>G
NM_001318088.2:c.537T>G
NM_001365135.2:c.1326T>G
NP_000534.3:p.Ser486Arg
NP_001007594.2:p.Ser485Arg
NP_001305016.1:p.Ser486Arg
NP_001305017.1:p.Ser179Arg
NP_001352064.1:p.Ser442Arg
NC_000011.9:g.6415243T>G
NM_000543.4:c.1458T>G
NR_027400.3:n.1411T>G
NR_134502.2:n.930T>G

Protein change:

S179R

Links:

dbSNP: rs281860665

NCBI 1000 Genomes Browser:

rs281860665

Molecular consequence:

NM_000543.5:c.1458T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001007593.3:c.1455T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001318087.2:c.1458T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001318088.2:c.537T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365135.2:c.1326T>G - missense variant - [Sequence Ontology: SO:0001583]
NR_027400.3:n.1411T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_134502.2:n.930T>G - 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

Recent activity

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Homo sapiens cDNA FLJ40801 fis, clone TRACH2008278
Homo sapiens cDNA FLJ40801 fis, clone TRACH2008278
gi|21758064|dbj|AK098120.1|

Nucleotide
H.sapiens U13 snRNA pseudogene U13.4B
H.sapiens U13 snRNA pseudogene U13.4B
gi|37521|emb|X58062.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000960204	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 21, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23356216, 28492532
SCV002788655	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 17, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000960204

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 21, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002788655

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 17, 2022)

unknown

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of a distinct mutation spectrum in the SMPD1 gene of Chinese patients with acid sphingomyelinase-deficient Niemann-Pick disease.

Zhang H, Wang Y, Gong Z, Li X, Qiu W, Han L, Ye J, Gu X.

Orphanet J Rare Dis. 2013 Jan 28;8:15. doi: 10.1186/1750-1172-8-15.

PubMed [citation]

PMID:: 23356216
PMCID:: PMC3566977

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

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000960204.4

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

Description

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. ClinVar contains an entry for this variant (Variation ID: 662004). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 23356216). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 486 of the SMPD1 protein (p.Ser486Arg).

#	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

From Fulgent Genetics, Fulgent Genetics, SCV002788655.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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