NM_000543.5(SMPD1):c.1253G>A (p.Arg418Gln) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 13, 2022
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:: RCV002222756.1

Allele description [Variation Report for NM_000543.5(SMPD1):c.1253G>A (p.Arg418Gln)]

NM_000543.5(SMPD1):c.1253G>A (p.Arg418Gln)

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.1253G>A (p.Arg418Gln)

HGVS:

NC_000011.10:g.6393377G>A
NG_011780.1:g.7953G>A
NG_029615.1:g.31038C>T
NM_000543.5:c.1253G>AMANE SELECT
NM_001007593.3:c.1250G>A
NM_001318087.2:c.1253G>A
NM_001318088.2:c.332G>A
NM_001365135.2:c.1132-240G>A
NP_000534.3:p.Arg418Gln
NP_001007594.2:p.Arg417Gln
NP_001305016.1:p.Arg418Gln
NP_001305017.1:p.Arg111Gln
NC_000011.9:g.6414607G>A
NM_000543.4:c.1253G>A
NR_134502.2:n.725G>A

Protein change:

R111Q

Links:

dbSNP: rs767722360

NCBI 1000 Genomes Browser:

rs767722360

Molecular consequence:

NM_001365135.2:c.1132-240G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000543.5:c.1253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001007593.3:c.1250G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318087.2:c.1253G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318088.2:c.332G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_134502.2:n.725G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002500349	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Mar 13, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30788890, 29140481 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002500349

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Mar 13, 2022)

germline

clinical testing

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

Citation Link

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

Citations

PubMed

SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease.

Alcalay RN, Mallett V, Vanderperre B, Tavassoly O, Dauvilliers Y, Wu RYJ, Ruskey JA, Leblond CS, Ambalavanan A, Laurent SB, Spiegelman D, Dionne-Laporte A, Liong C, Levy OA, Fahn S, Waters C, Kuo SH, Chung WK, Ford B, Marder KS, Kang UJ, Hassin-Baer S, et al.

Mov Disord. 2019 Apr;34(4):526-535. doi: 10.1002/mds.27642. Epub 2019 Feb 20.

PubMed [citation]

PMID:: 30788890
PMCID:: PMC6469643

Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease.

Robak LA, Jansen IE, van Rooij J, Uitterlinden AG, Kraaij R, Jankovic J; International Parkinson’s Disease Genomics Consortium (IPDGC)., Heutink P, Shulman JM.

Brain. 2017 Dec 1;140(12):3191-3203. doi: 10.1093/brain/awx285.

PubMed [citation]

PMID:: 29140481
PMCID:: PMC5841393

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002500349.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: SMPD1 c.1253G>A (p.Arg418Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 248074 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SMPD1 causing Niemann-Pick Disease (6e-05 vs 0.0022), allowing no conclusion about variant significance. c.1253G>A has been reported in the literature as a non-informative genotype (second allele not reported/specified) among cohorts of patients with Parkinson Disease (example, Robak_2017, Alcalay_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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: Mar 16, 2024

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