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NM_000543.5(SMPD1):c.748A>C (p.Ser250Arg) AND not specified

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 9, 2018
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:
RCV000780730.1

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)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000918240Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Feb 9, 2018) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

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
See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918240.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: SMPD1 c.748A>C (p.Ser250Arg) results in a non-conservative amino acid change located in ApaH type Calcineurin-like phosphoesterase domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 244428 control chromosomes in gnomAD. This frequency is not significantly higher than expected for a pathogenic variant in SMPD1 causing Niemann-Pick Disease (1.7e-05 vs 0.0022), allowing no conclusion about variant significance. c.748A>C has been reported in the literature in individuals affected with Niemann-Pick Disease Type A and B (Hollak_2012, Zhang_2013, Toth_2011, Diggelen_2005). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Hollak_2012). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024