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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002060343	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Uncertain significance (Nov 10, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002312727	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 21, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 26499107, 12369017, 12712061, 15234149, 23252888, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002060343

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))

Uncertain significance
(Nov 10, 2021)

unknown

clinical testing

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

Citation Link,

SCV002312727

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 21, 2024)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	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

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	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

Last Updated: Nov 30, 2024

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