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

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jan 21, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV001810448.15

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)

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002060343Myriad Genetics, Inc.
criteria provided, single submitter

(Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))
Uncertain significance
(Nov 10, 2021)
unknownclinical testing

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

Citation Link,

SCV002312727Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Jan 21, 2024)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

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

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
See all PubMed Citations (6)

Details of each submission

From Myriad Genetics, Inc., SCV002060343.2

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

Description

NM_000543.4(SMPD1):c.1427G>A(R476Q) is a missense variant classified as a variant of uncertain significance in the context of Niemann-Pick disease, SMPD1-related. R476Q has been observed in cases with relevant disease (PMID: 26499107). Functional assessments of this variant are not available in the literature. R476Q has been observed in population frequency databases (gnomAD: SAS 0.02%). In summary, there is insufficient evidence to classify NM_000543.4(SMPD1):c.1427G>A(R476Q) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002312727.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces arginine with glutamine at codon 476 of the SMPD1 protein (p.Arg476Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs763566905, gnomAD 0.02%). This variant has been observed in individual(s) with SMPD1-related conditions (PMID: 26499107). ClinVar contains an entry for this variant (Variation ID: 385606). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg476 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12369017, 12712061, 15234149, 23252888; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Nov 30, 2024