ClinVar Genomic variation as it relates to human health
NM_000543.5(SMPD1):c.1550A>T (p.Glu517Val)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(8); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000543.5(SMPD1):c.1550A>T (p.Glu517Val)
Variation ID: 198094 Accession: VCV000198094.59
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 6394261 (GRCh38) [ NCBI UCSC ] 11: 6415491 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 6, 2016 Aug 4, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000543.5(SMPD1):c.1550A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000543.5:c.1550A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000534.3:p.Glu517Val missense NM_001007593.3:c.1547A>T NP_001007594.2:p.Glu516Val missense NM_001318087.2:c.*43A>T 3 prime UTR NM_001318088.2:c.629A>T NP_001305017.1:p.Glu210Val missense NM_001365135.2:c.1418A>T NP_001352064.1:p.Glu473Val missense NR_027400.3:n.1503A>T non-coding transcript variant NR_134502.2:n.1042A>T non-coding transcript variant NC_000011.10:g.6394261A>T NC_000011.9:g.6415491A>T NG_011780.1:g.8837A>T NG_029615.1:g.30154T>A - Protein change
- E517V, E473V, E516V, E210V
- Other names
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- Canonical SPDI
- NC_000011.10:6394260:A:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00140 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00140
1000 Genomes Project 30x 0.00203
The Genome Aggregation Database (gnomAD), exomes 0.00229
Exome Aggregation Consortium (ExAC) 0.00231
Trans-Omics for Precision Medicine (TOPMed) 0.00250
The Genome Aggregation Database (gnomAD) 0.00284
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00323
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SMPD1 | - | - |
GRCh38 GRCh37 |
985 | 1054 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Dec 7, 2023 | RCV000179328.19 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV001081864.15 | |
Uncertain significance (7) |
criteria provided, multiple submitters, no conflicts
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Oct 2, 2023 | RCV000962425.40 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001107855.12 | |
Uncertain significance (2) |
criteria provided, single submitter
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Jan 22, 2020 | RCV001249037.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 11, 2018 | RCV001786338.9 | |
SMPD1-related disorder
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Likely benign (1) |
criteria provided, single submitter
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Feb 3, 2022 | RCV003967440.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Sphingomyelin/cholesterol lipidosis
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422972.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022 |
Comment:
The p.Glu517Val variant in SMPD1 (also known as p.Glu515Val due to a difference in cDNA numbering) has been reported in at least 2 individuals with … (more)
The p.Glu517Val variant in SMPD1 (also known as p.Glu515Val due to a difference in cDNA numbering) has been reported in at least 2 individuals with Niemann-Pick disease (PMID: 23430949, 26049896) and has been identified in 0.410% (529/129080) of European (non-Finnish) chromosomes, including 2 homozygotes, 0.192% (68/35430) of Latino chromosomes, and 0.108% (27/24970) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142787001). This variant has also been reported in ClinVar (VariationID: 198094) as likely benign by EGL Genetic Diagnostics and as a VUS by ARUP Laboratories and Integrated Genetics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a reported pathogenic variant and in an individual with Niemann-Pick disease increases the likelihood that the p.Glu517Val variant is pathogenic (VariationID: 2994; PMID: 23430949). In summary, the clinical significance of the p.Glu517Val variant is uncertain. ACMG/AMP Criteria applied: BS1, PP3, PM3_Supporting (Richards 2015). (less)
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Uncertain significance
(Oct 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605228.3
First in ClinVar: Dec 06, 2016 Last updated: Feb 20, 2024 |
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Uncertain significance
(Jul 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001148166.25
First in ClinVar: Feb 03, 2020 Last updated: Aug 04, 2024 |
Comment:
SMPD1: PS4:Supporting
Number of individuals with the variant: 2
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Likely benign
(Jan 06, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000231560.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 10
Sex: mixed
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type A
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001265042.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Jun 11, 2018)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type B
Affected status: unknown
Allele origin:
germline
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Centogene AG - the Rare Disease Company
Accession: SCV002028334.1
First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021 |
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Uncertain significance
(Jan 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV003194900.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
Reported as E515V due to the use of alternative nomenclature in association with Niemann-Pick disease; however, additional information was not provided (Simonaro et al., 2002); … (more)
Reported as E515V due to the use of alternative nomenclature in association with Niemann-Pick disease; however, additional information was not provided (Simonaro et al., 2002); Reported in association with Parkinson disease; however, additional information was not provided and the variant was observed in unaffected control individuals (Robak et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31122880, 23430949, 26049896, 34426522, 12369017, 29140481, 35747619, 30788890) (less)
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Uncertain significance
(Feb 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002541123.2
First in ClinVar: Jul 09, 2022 Last updated: Jan 26, 2024 |
Comment:
BS1, PP3
Number of individuals with the variant: 4
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Uncertain significance
(Dec 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000920238.3
First in ClinVar: Jun 02, 2019 Last updated: Feb 04, 2024 |
Comment:
Variant summary: SMPD1 c.1550A>T (p.Glu517Val) results in a non-conservative amino acid change located in the Sphingomyelin phosphodiesterase, C-terminal domain (IPR045473) of the encoded protein sequence. … (more)
Variant summary: SMPD1 c.1550A>T (p.Glu517Val) results in a non-conservative amino acid change located in the Sphingomyelin phosphodiesterase, C-terminal domain (IPR045473) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 251358 control chromosomes, predominantly at a frequency of 0.0037 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.65 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMPD1 causing Niemann-Pick Disease Type A phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European originc.1550A>T has been reported in the literature in compound heterozygous individuals affected with Niemann-Pick Disease Type A (e.g. Wittmann_2012, Wasserstein_2015) and in several other patients without strong evidence for causality (e.g. Simonaro_2002, Zampieri_2015, Clark_2015). These reports do not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease Type A and indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12369017, 24767253, 23430949, 26499107, 26049896, 25933391).Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; eight submitters classified the variant as uncertain significance, while two classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Likely benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type B
Niemann-Pick disease, type A
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001109504.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 28, 2024 |
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Likely benign
(Feb 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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SMPD1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004789061.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001974273.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001806957.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Uncertain significance
(May 04, 2017)
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no assertion criteria provided
Method: clinical testing
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Acid sphingomyelinase deficiency
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001452643.1
First in ClinVar: Jan 01, 2021 Last updated: Jan 01, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001928360.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genome Sequencing in the Parkinson Disease Clinic. | Hill EJ | Neurology. Genetics | 2022 | PMID: 35747619 |
Niemann-Pick disease A or B in four pediatric patients and SMPD1 mutation carrier frequency in the Mexican population. | Cerón-Rodríguez M | Annals of hepatology | 2019 | PMID: 31122880 |
SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease. | Alcalay RN | Movement disorders : official journal of the Movement Disorder Society | 2019 | PMID: 30788890 |
Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. | Robak LA | Brain : a journal of neurology | 2017 | PMID: 29140481 |
SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants. | Zampieri S | Human mutation | 2016 | PMID: 26499107 |
Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency. | Wasserstein MP | Molecular genetics and metabolism | 2015 | PMID: 26049896 |
Gene-wise association of variants in four lysosomal storage disorder genes in neuropathologically confirmed Lewy body disease. | Clark LN | PloS one | 2015 | PMID: 25933391 |
Assessment of a targeted resequencing assay as a support tool in the diagnosis of lysosomal storage disorders. | Fernández-Marmiesse A | Orphanet journal of rare diseases | 2014 | PMID: 24767253 |
Newborn screening for lysosomal storage disorders in hungary. | Wittmann J | JIMD reports | 2012 | PMID: 23430949 |
The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations. | Simonaro CM | American journal of human genetics | 2002 | PMID: 12369017 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SMPD1 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/5ef665fb-0538-45a0-aded-826f7dd47f24 | - | - | - | - |
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Text-mined citations for rs142787001 ...
HelpRecord last updated Sep 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.