NM_000543.5(SMPD1):c.748A>C (p.Ser250Arg) AND multiple conditions

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jul 22, 2021
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:: RCV001250174.9

Allele description [Variation Report for NM_000543.5(SMPD1):c.748A>C (p.Ser250Arg)]

NM_000543.5(SMPD1):c.748A>C (p.Ser250Arg)

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.748A>C (p.Ser250Arg)

HGVS:

NC_000011.10:g.6391813A>C
NG_011780.1:g.6389A>C
NM_000543.5:c.748A>CMANE SELECT
NM_001007593.3:c.745A>C
NM_001318087.2:c.748A>C
NM_001318088.2:c.-214A>C
NM_001365135.2:c.748A>C
NP_000534.3:p.Ser250Arg
NP_001007594.2:p.Ser249Arg
NP_001305016.1:p.Ser250Arg
NP_001352064.1:p.Ser250Arg
NC_000011.9:g.6413043A>C
NM_000543.4(SMPD1):c.748A>C
NM_000543.4:c.748A>C
NR_027400.3:n.873A>C
p.Ser250Arg

Protein change:

S249R

Links:

dbSNP: rs750779804

NCBI 1000 Genomes Browser:

rs750779804

Molecular consequence:

NM_001318088.2:c.-214A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000543.5:c.748A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001007593.3:c.745A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001318087.2:c.748A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001365135.2:c.748A>C - missense variant - [Sequence Ontology: SO:0001583]
NR_027400.3:n.873A>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
SCV001424499	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001592860	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 3, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12556236, 15877209, 16642440, 23430884, 28492532
SCV002810896	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 22, 2021)	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

SCV001424499

Centogene AG - the Rare Disease Company

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

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

SCV001592860

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 3, 2020)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002810896

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 22, 2021)

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	germline	yes	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Seven novel acid sphingomyelinase gene mutations in Niemann-Pick type A and B patients.

Sikora J, Pavlu-Pereira H, Elleder M, Roelofs H, Wevers RA.

Ann Hum Genet. 2003 Jan;67(Pt 1):63-70.

PubMed [citation]

PMID:: 12556236

Acid sphingomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty-five Czech and Slovak patients. A multi-approach study.

Pavlů-Pereira H, Asfaw B, Poupctová H, Ledvinová J, Sikora J, Vanier MT, Sandhoff K, Zeman J, Novotná Z, Chudoba D, Elleder M.

J Inherit Metab Dis. 2005;28(2):203-27.

PubMed [citation]

PMID:: 15877209

See all PubMed Citations (6)

Details of each submission

From Centogene AG - the Rare Disease Company, SCV001424499.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001592860.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect SMPD1 protein function (PMID: 16642440). This variant has been observed in individual(s) with Niemann-Pick disease (PMID: 12556236, 15877209, 16642440, 23430884). This variant is also known as g.1208A>C, c.742A>C (S248R) in the literature. ClinVar contains an entry for this variant (Variation ID: 371576). This variant is present in population databases (rs750779804, ExAC 0.006%). This sequence change replaces serine with arginine at codon 250 of the SMPD1 protein (p.Ser250Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine.

#	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, SCV002810896.1

#	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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