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NM_000543.5(SMPD1):c.1427G>A (p.Arg476Gln) AND not specified

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jan 7, 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:
RCV003114556.10

Allele description [Variation Report for NM_000543.5(SMPD1):c.1427G>A (p.Arg476Gln)]

NM_000543.5(SMPD1):c.1427G>A (p.Arg476Gln)

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.1427G>A (p.Arg476Gln)
HGVS:
  • NC_000011.10:g.6393982G>A
  • NG_011780.1:g.8558G>A
  • NG_029615.1:g.30433C>T
  • NM_000543.4(SMPD1):c.1427G>A
  • NM_000543.5:c.1427G>AMANE SELECT
  • NM_001007593.3:c.1424G>A
  • NM_001318087.2:c.1427G>A
  • NM_001318088.2:c.506G>A
  • NM_001365135.2:c.1295G>A
  • NP_000534.3:p.Arg476Gln
  • NP_001007594.2:p.Arg475Gln
  • NP_001305016.1:p.Arg476Gln
  • NP_001305017.1:p.Arg169Gln
  • NP_001352064.1:p.Arg432Gln
  • NC_000011.9:g.6415212G>A
  • NC_000011.9:g.6415212G>A
  • NM_000543.4(SMPD1):c.1427G>A
  • NM_000543.4:c.1427G>A
  • NR_027400.3:n.1380G>A
  • NR_134502.2:n.899G>A
  • p.Arg476Gln
Protein change:
R169Q
Links:
dbSNP: rs763566905
NCBI 1000 Genomes Browser:
rs763566905
Molecular consequence:
  • NM_000543.5:c.1427G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001007593.3:c.1424G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318087.2:c.1427G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318088.2:c.506G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001365135.2:c.1295G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_027400.3:n.1380G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_134502.2:n.899G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV003800814Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Uncertain significance
(Jan 7, 2023)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants.

Zampieri S, Filocamo M, Pianta A, Lualdi S, Gort L, Coll MJ, Sinnott R, Geberhiwot T, Bembi B, Dardis A.

Hum Mutat. 2016 Feb;37(2):139-47. doi: 10.1002/humu.22923. Epub 2015 Dec 1. Review.

PubMed [citation]
PMID:
26499107

Crystal structure of mammalian acid sphingomyelinase.

Gorelik A, Illes K, Heinz LX, Superti-Furga G, Nagar B.

Nat Commun. 2016 Jul 20;7:12196. doi: 10.1038/ncomms12196.

PubMed [citation]
PMID:
27435900
PMCID:
PMC4961792

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003800814.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: SMPD1 c.1427G>A (p.Arg476Gln) results in a conservative amino acid change located in the Acid sphingomyelinase/endopolyphosphatase, metallophosphatase domain (IPR041805) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251486 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1427G>A has been reported in the literature in one compound heterozygous individual affected with Niemann-Pick Disease (Zampieri_2015). These data do not allow any conclusion about variant significance. The variant is predicted to impact protein folding/stability when modelled using the crystal structure of the SMPD1 protein (Gorelik_2016). However, without experimental validation, this does not allow convincing conclusions about the variants' effect on protein function. A different substitution at the same codon has been previously classified as pathogenic by our laboratory (c.1426C>T [p.Arg476Trp], ClinVar: 93315), suggesting this residue is important for normal function. Six ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, and five as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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

Last Updated: Nov 30, 2024