ClinVar Genomic variation as it relates to human health
NM_000543.5(SMPD1):c.475T>C (p.Cys159Arg)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000543.5(SMPD1):c.475T>C (p.Cys159Arg)
Variation ID: 167709 Accession: VCV000167709.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 6391540 (GRCh38) [ NCBI UCSC ] 11: 6412770 (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 Jun 28, 2015 Jun 17, 2024 Mar 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000543.5:c.475T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000534.3:p.Cys159Arg missense NM_001007593.3:c.472T>C NP_001007594.2:p.Cys158Arg missense NM_001318087.2:c.475T>C NP_001305016.1:p.Cys159Arg missense NM_001318088.2:c.-487T>C 5 prime UTR NM_001365135.2:c.475T>C NP_001352064.1:p.Cys159Arg missense NR_027400.3:n.600T>C non-coding transcript variant NC_000011.10:g.6391540T>C NC_000011.9:g.6412770T>C NG_011780.1:g.6116T>C - Protein change
- C159R, C158R
- Other names
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- Canonical SPDI
- NC_000011.10:6391539:T:C
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Exome Aggregation Consortium (ExAC) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
980 | 1049 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 26, 2024 | RCV000153979.16 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 10, 2023 | RCV000723416.14 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2024 | RCV001045638.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 22, 2020 | RCV001248935.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 4, 2023 | RCV001174779.12 |
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
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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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Pathogenic
(Dec 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type A
Niemann-Pick disease, type B
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002776605.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Apr 04, 2023)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001338109.4
First in ClinVar: Jun 22, 2020 Last updated: Jun 03, 2023 |
Comment:
Variant summary: SMPD1 c.475T>C (p.Cys159Arg) results in a non-conservative amino acid change located in the Saposin B type domain (IPR008139) of the encoded protein sequence. … (more)
Variant summary: SMPD1 c.475T>C (p.Cys159Arg) results in a non-conservative amino acid change located in the Saposin B type domain (IPR008139) of the encoded protein sequence. This domain has been reported to have functional importance for ASM catalytic activity (Simonaro_2002). Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250578 control chromosomes (gnomAD). c.475T>C has been reported in the literature in individuals affected with Niemann-Pick disease type B and subsequently cited by others (e.g. McGovern_2004). These data indicate that the variant may be associated with disease. The variant has also been detected in individuals affected with Parkinsons's Disease, without strong evidence for causality (e.g. Robak_2017, Alcalay_2019). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of catalytic activity (10%-<30% of normal activity) in vitro (Ida_1993). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Jul 10, 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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Revvity Omics, Revvity
Accession: SCV004238690.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 18, 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: SCV001209502.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 159 of the SMPD1 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 159 of the SMPD1 protein (p.Cys159Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 16434659, 17011332; Invitae). This variant is also known as C157R, c.463T>C (p.Cys155Arg) . ClinVar contains an entry for this variant (Variation ID: 167709). 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%. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 8407868). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 26, 2024)
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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:
unknown
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Baylor Genetics
Accession: SCV004205059.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Likely pathogenic
(Aug 22, 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:
unknown
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Counsyl
Accession: SCV000793590.1
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
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Pathogenic
(Apr 25, 2014)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000203604.7
First in ClinVar: Jan 30, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 6
Sex: mixed
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Pathogenic
(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: SCV001422713.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022 |
Comment:
The p.Cys159Arg variant in SMPD1 (also known as p.Cys157Arg due to a difference in cDNA numbering) has been reported in at least 3 individuals with … (more)
The p.Cys159Arg variant in SMPD1 (also known as p.Cys157Arg due to a difference in cDNA numbering) has been reported in at least 3 individuals with Niemann-Pick disease (PMID: 12369017, 16434659, 17011332) and has been identified in 0.010% (1/10348) of Ashkenazi Jewish chromosomes, 0.004% (1/24922) of African chromosomes, and 0.002% (3/128714) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727504166). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also has also been reported in ClinVar (VariationID: 167709) as likely pathogenic by Counsyl and Integrated Genetics and as pathogenic by EGL Genetic Diagnostics. In vitro functional studies provide some evidence that the p.Cys159Arg variant may impact protein function (PMID: 8407868). However, these types of assays may not accurately represent biological function. 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.Cys159Arg variant is pathogenic (VariationID: 2993; 16434659). The p.Cys159Arg variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 12369017, 27725636). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on functional studies, its location in a disulfide bond in the saposin domain, and the presence of the variant in combination with another pathogenic variant. ACMG/AMP Criteria applied: PS3, PM2, PM1, PP3, PM3_supporting (Richards 2015). (less)
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Likely pathogenic
(Sep 21, 2020)
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no assertion criteria provided
Method: clinical testing
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Niemann-Pick Disease, Types A/B
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002091679.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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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 |
Human acid sphingomyelinase structures provide insight to molecular basis of Niemann-Pick disease. | Zhou YF | Nature communications | 2016 | PMID: 27725636 |
SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants. | Zampieri S | Human mutation | 2016 | PMID: 26499107 |
Acid sphingomyelinase deficiency: prevalence and characterization of an intermediate phenotype of Niemann-Pick disease. | Wasserstein MP | The Journal of pediatrics | 2006 | PMID: 17011332 |
Natural history of Type A Niemann-Pick disease: possible endpoints for therapeutic trials. | McGovern MM | Neurology | 2006 | PMID: 16434659 |
Functional characterization of the postulated intramolecular sphingolipid activator protein domain of human acid sphingomyelinase. | Kölzer M | Biological chemistry | 2004 | PMID: 15653433 |
The natural history of type B Niemann-Pick disease: results from a 10-year longitudinal study. | Wasserstein MP | Pediatrics | 2004 | PMID: 15545621 |
Ocular manifestations of Niemann-Pick disease type B. | McGovern MM | Ophthalmology | 2004 | PMID: 15234149 |
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 |
Cloning of a human acid sphingomyelinase cDNA with a new mutation that renders the enzyme inactive. | Ida H | Journal of biochemistry | 1993 | PMID: 8407868 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SMPD1 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/837d1cca-fa88-4e9b-b9a7-6a366ecb79c8 | - | - | - | - |
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Text-mined citations for rs727504166 ...
HelpRecord last updated Jul 15, 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.