Variant summary: SMPD1 c.96G>A (p.Trp32X) results in a premature termination codon, predicted to cause an N-terminal truncation of the encoded protein due to translation initiation at a downstream START codon or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 239304 control chromosomes (gnomAD). c.96G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Niemann-Pick Disease Type B (Pittis_2004, Bonetto_2005, Fotoulaki_2007, Irun_2013, Romanello_2016). These data indicate that the variant is very likely to be associated with disease. Publications reported experimental evidence evaluating an impact on protein function, demonstrating a residual enzyme activity of ~20% in leukocytes derived from a homozygous patient (Pittis_2004), though a complete lack of enzyme activity was reported in a eukaryotic cell expression system (Dardis_2005). 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 pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000543.5(SMPD1):c.96G>A (p.Trp32Ter)
Germline
Classification
Help
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.
(8)
Help
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.
Pathogenic/Likely pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000543.5(SMPD1):c.96G>A (p.Trp32Ter)
Variation ID: 188840 Accession: VCV000188840.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 6390694 (GRCh38) [ NCBI UCSC ] 11: 6411924 (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 Mar 29, 2015 Jan 25, 2025 Apr 4, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000543.5:c.96G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000534.3:p.Trp32Ter nonsense NM_001007593.3:c.96G>A NP_001007594.2:p.Trp32Ter nonsense NM_001318087.2:c.96G>A NP_001305016.1:p.Trp32Ter nonsense NM_001318088.2:c.-866G>A 5 prime UTR NM_001365135.2:c.96G>A NP_001352064.1:p.Trp32Ter nonsense NR_027400.3:n.221G>A non-coding transcript variant NR_134502.2:n.221G>A non-coding transcript variant NC_000011.10:g.6390694G>A NC_000011.9:g.6411924G>A NG_011780.1:g.5270G>A - Protein change
- W32*
- Other names
- -
- Canonical SPDI
- NC_000011.10:6390693:G:A
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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
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| SMPD1 | - | - |
GRCh38 GRCh37 |
1017 | 1086 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000169189.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 1, 2020 | RCV001199862.1 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 4, 2024 | RCV001219345.10 | |
|
SMPD1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
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Jan 13, 2024 | RCV003947446.2 |
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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|---|---|---|---|---|---|
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Pathogenic
(May 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Niemann-Pick disease, type B
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001370598.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
Variant summary: SMPD1 c.96G>A (p.Trp32X) results in a premature termination codon, predicted to cause an N-terminal truncation of the encoded protein due to translation initiation … (more)
Variant summary: SMPD1 c.96G>A (p.Trp32X) results in a premature termination codon, predicted to cause an N-terminal truncation of the encoded protein due to translation initiation at a downstream START codon or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 239304 control chromosomes (gnomAD). c.96G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Niemann-Pick Disease Type B (Pittis_2004, Bonetto_2005, Fotoulaki_2007, Irun_2013, Romanello_2016). These data indicate that the variant is very likely to be associated with disease. Publications reported experimental evidence evaluating an impact on protein function, demonstrating a residual enzyme activity of ~20% in leukocytes derived from a homozygous patient (Pittis_2004), though a complete lack of enzyme activity was reported in a eukaryotic cell expression system (Dardis_2005). 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 pathogenic. (less)
|
|
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Likely pathogenic
(Jun 20, 2014)
|
criteria provided, single submitter
Method: literature only
|
Niemann-Pick disease, type A
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220433.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
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Pathogenic
(Jul 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001391280.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp32*) in the SMPD1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Trp32*) in the SMPD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Niemann-Pick disease (PMID: 15241805, 17876723). ClinVar contains an entry for this variant (Variation ID: 188840). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Nov 02, 2023)
|
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: SCV004205536.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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|
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Pathogenic
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Niemann-Pick disease, type A
Niemann-Pick disease, type B
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
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002806505.2
First in ClinVar: Dec 31, 2022 Last updated: Jan 25, 2025 |
|
|
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Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: curation
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Niemann-Pick disease, type A
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051975.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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|
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Pathogenic
(Jan 13, 2024)
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no assertion criteria provided
Method: clinical testing
|
SMPD1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004758120.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The SMPD1 c.96G>A variant is predicted to result in premature protein termination (p.Trp32*). This variant has been reported in the homozygous and compound heterozygous states … (more)
The SMPD1 c.96G>A variant is predicted to result in premature protein termination (p.Trp32*). This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with Niemann-Pick disease type B (see for example, Table 1, Pittis et al. 2004. PubMed ID: 15241805; Fotoulaki et al. 2007. PubMed ID: 17876723; Table 1, Irun et al. 2013. PubMed ID: 23252888). This variant has not been reported in a large population database, indicating this variant is rare. In vitro experimental studies suggest this variant decreases enzymatic activity of the protein (Dardis et al. 2005. PubMed ID: 16010684). Nonsense variants in SMPD1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
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Pathogenic
(Dec 06, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Niemann-Pick Disease, Types A/B
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002091654.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Trp32*) in the SMPD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Niemann-Pick disease (PMID: 15241805, 17876723). ClinVar contains an entry for this variant (Variation ID: 188840). For these reasons, this variant has been classified as Pathogenic.
Comment:
The SMPD1 c.96G>A variant is predicted to result in premature protein termination (p.Trp32*). This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with Niemann-Pick disease type B (see for example, Table 1, Pittis et al. 2004. PubMed ID: 15241805; Fotoulaki et al. 2007. PubMed ID: 17876723; Table 1, Irun et al. 2013. PubMed ID: 23252888). This variant has not been reported in a large population database, indicating this variant is rare. In vitro experimental studies suggest this variant decreases enzymatic activity of the protein (Dardis et al. 2005. PubMed ID: 16010684). Nonsense variants in SMPD1 are expected to be pathogenic. This variant is interpreted as pathogenic.
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. |
Comment:
Variant summary: SMPD1 c.96G>A (p.Trp32X) results in a premature termination codon, predicted to cause an N-terminal truncation of the encoded protein due to translation initiation at a downstream START codon or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 239304 control chromosomes (gnomAD). c.96G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Niemann-Pick Disease Type B (Pittis_2004, Bonetto_2005, Fotoulaki_2007, Irun_2013, Romanello_2016). These data indicate that the variant is very likely to be associated with disease. Publications reported experimental evidence evaluating an impact on protein function, demonstrating a residual enzyme activity of ~20% in leukocytes derived from a homozygous patient (Pittis_2004), though a complete lack of enzyme activity was reported in a eukaryotic cell expression system (Dardis_2005). 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 pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Trp32*) in the SMPD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Niemann-Pick disease (PMID: 15241805, 17876723). ClinVar contains an entry for this variant (Variation ID: 188840). For these reasons, this variant has been classified as Pathogenic.
Comment:
The SMPD1 c.96G>A variant is predicted to result in premature protein termination (p.Trp32*). This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with Niemann-Pick disease type B (see for example, Table 1, Pittis et al. 2004. PubMed ID: 15241805; Fotoulaki et al. 2007. PubMed ID: 17876723; Table 1, Irun et al. 2013. PubMed ID: 23252888). This variant has not been reported in a large population database, indicating this variant is rare. In vitro experimental studies suggest this variant decreases enzymatic activity of the protein (Dardis et al. 2005. PubMed ID: 16010684). Nonsense variants in SMPD1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Comprehensive Evaluation of Plasma 7-Ketocholesterol and Cholestan-3β,5α,6β-Triol in an Italian Cohort of Patients Affected by Niemann-Pick Disease due to NPC1 and SMPD1 Mutations. | Romanello M | Clinica chimica acta; international journal of clinical chemistry | 2016 | PMID: 26790753 |
| SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants. | Zampieri S | Human mutation | 2016 | PMID: 26499107 |
| Identification of seven novel SMPD1 mutations causing Niemann-Pick disease types A and B. | Irun P | Clinical genetics | 2013 | PMID: 23252888 |
| A prospective, cross-sectional survey study of the natural history of Niemann-Pick disease type B. | McGovern MM | Pediatrics | 2008 | PMID: 18625664 |
| Acid sphingomyelinase-deficient Niemann-Pick disease: novel findings in a Greek child. | Fotoulaki M | Journal of inherited metabolic disease | 2007 | PMID: 17876723 |
| A 3-year-old child with abdominal pain and fever. | Bonetto G | The European respiratory journal | 2005 | PMID: 16264060 |
| Functional in vitro characterization of 14 SMPD1 mutations identified in Italian patients affected by Niemann Pick Type B disease. | Dardis A | Human mutation | 2005 | PMID: 16010684 |
| Acid sphingomyelinase: identification of nine novel mutations among Italian Niemann Pick type B patients and characterization of in vivo functional in-frame start codon. | Pittis MG | Human mutation | 2004 | PMID: 15241805 |
| Screening of 25 Italian patients with Niemann-Pick A reveals fourteen new mutations, one common and thirteen private, in SMPD1. | Ricci V | Human mutation | 2004 | PMID: 15221801 |
| 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 |
| Occurrence of two molecular forms of human acid sphingomyelinase. | Ferlinz K | The Biochemical journal | 1994 | PMID: 8053910 |
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Text-mined citations for rs786204506 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jan 26, 2025
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.