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NM_000543.5(SMPD1):c.592G>C (p.Ala198Pro) AND Sphingomyelin/cholesterol lipidosis

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jan 22, 2020
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:
RCV000192220.14

Allele description [Variation Report for NM_000543.5(SMPD1):c.592G>C (p.Ala198Pro)]

NM_000543.5(SMPD1):c.592G>C (p.Ala198Pro)

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.592G>C (p.Ala198Pro)
HGVS:
  • NC_000011.10:g.6391657G>C
  • NG_011780.1:g.6233G>C
  • NM_000543.4(SMPD1):c.592G>C
  • NM_000543.5:c.592G>CMANE SELECT
  • NM_001007593.3:c.589G>C
  • NM_001318087.2:c.592G>C
  • NM_001318088.2:c.-370G>C
  • NM_001365135.2:c.592G>C
  • NP_000534.3:p.Ala198Pro
  • NP_000534.3:p.Ala198Pro
  • NP_001007594.2:p.Ala197Pro
  • NP_001305016.1:p.Ala198Pro
  • NP_001352064.1:p.Ala198Pro
  • NC_000011.9:g.6412887G>C
  • NM_000543.3:c.592G>C
  • NM_000543.4(SMPD1):c.592G>C
  • NM_000543.4:c.592G>C
  • NM_000543.5:c.592G>C
  • NR_027400.3:n.717G>C
  • p.Ala196Pro
Protein change:
A197P
Links:
dbSNP: rs797044798
NCBI 1000 Genomes Browser:
rs797044798
Molecular consequence:
  • NM_001318088.2:c.-370G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000543.5:c.592G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001007593.3:c.589G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318087.2:c.592G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365135.2:c.592G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_027400.3:n.717G>C - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000238487GeneReviews
no classification provided
not providedgermlineliterature only

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

SCV001422712Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Jan 22, 2020) 		germlinecuration

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedliterature only, curation

Citations

PubMed

The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations.

Simonaro CM, Desnick RJ, McGovern MM, Wasserstein MP, Schuchman EH.

Am J Hum Genet. 2002 Dec;71(6):1413-9. Epub 2002 Oct 4.

PubMed [citation]
PMID:
12369017
PMCID:
PMC378582

Ocular manifestations of Niemann-Pick disease type B.

McGovern MM, Wasserstein MP, Aron A, Desnick RJ, Schuchman EH, Brodie SE.

Ophthalmology. 2004 Jul;111(7):1424-7.

PubMed [citation]
PMID:
15234149
See all PubMed Citations (3)

Details of each submission

From GeneReviews, SCV000238487.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

Some evidence suggests that this pathogenic variant is associated with a less severe form of Niemann-Pick disease type B

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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422712.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (3)

Description

The p.Ala198Pro variant in SMPD1 has been reported in at least 10 individuals with Niemann-Pick disease (PMID: 15234149, 12369017) and has been identified in 0.001133% (1/88272) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs797044798). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 203435) as Pathogenic by GeneReviews. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The presence of this variant in 2 affected homozygotes and in combination with a reported pathogenic variant in at least 3 individuals with NIemann-Pick disease increases the likelihood that the p.Ala198Pro variant is pathogenic (VariationID: 167709, 100731; PMID: 15234149, 12369017). In summary, the clinical significance of the p.Ala198Pro variant is uncertain. ACMG/AMP Criteria applied: PM3_strong, PM2, BP4 (Richards 2015).

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

Last Updated: Nov 10, 2024