ClinVar Genomic variation as it relates to human health
NM_000543.5(SMPD1):c.1092-1G>C
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.1092-1G>C
Variation ID: 93312 Accession: VCV000093312.43
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 6393215 (GRCh38) [ NCBI UCSC ] 11: 6414445 (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 Oct 8, 2024 Mar 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000543.5:c.1092-1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001007593.3:c.1089-1G>C splice acceptor NM_001318087.2:c.1092-1G>C splice acceptor NM_001318088.2:c.171-1G>C splice acceptor NM_001365135.2:c.1132-402G>C intron variant NC_000011.10:g.6393215G>C NC_000011.9:g.6414445G>C NG_011780.1:g.7791G>C NG_029615.1:g.31200C>G - Protein change
- Other names
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- Canonical SPDI
- NC_000011.10:6393214:G: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 |
991 | 1060 |
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
Help
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 (3) |
criteria provided, multiple submitters, no conflicts
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Nov 11, 2022 | RCV000177083.30 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 19, 2024 | RCV000410331.6 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 16, 2020 | RCV001273166.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 14, 2023 | RCV001380609.6 |
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
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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
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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
(Jan 12, 2016)
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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: SCV000228903.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 4
Sex: mixed
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Pathogenic
(Dec 09, 2020)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918239.3
First in ClinVar: Jun 02, 2019 Last updated: Jan 05, 2021 |
Comment:
Variant summary: SMPD1 c.1092-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: SMPD1 c.1092-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. In support of these predictions, a functional study reported the variant to cause skipping of exon 3, resulting in a catalytically inactive ASM protein in cell-based assays (Levran_1993). The variant was absent in 248962 control chromosomes (gnomAD). c.1092-1G>C, has been reported in the literature in individuals affected with Niemann-Pick Disease Type A and Type B, one of whom was homozygous for the variant and was reported to have a severe phenotype of Type A (Levran_1993, Lipinski_2019, Wasserstein_2006). These data indicate that the variant is likely to be associated with disease. Peripheral blood leukocytes of a patient carrying the variant and also, c.496G>A (p.Gly166Arg) were determined to have 20% ASM residual activity (Lipinski_2019). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Apr 21, 2016)
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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: SCV000486242.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Nov 11, 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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GeneDx
Accession: SCV002601217.2
First in ClinVar: Nov 19, 2022 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed … (more)
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26499107, 30795770, 8499909) (less)
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Pathogenic
(Nov 14, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001578729.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 2 of the SMPD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects an acceptor splice site in intron 2 of the SMPD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individuals with acid sphingomyelinase deficiency (PMID: 8499909, 17011332, 30795770). This variant is also known as g2610c, IVS2-1G>C. ClinVar contains an entry for this variant (Variation ID: 93312). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 19, 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: SCV001163674.2
First in ClinVar: Feb 29, 2020 Last updated: Jun 17, 2024 |
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Pathogenic
(Jul 01, 2020)
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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: SCV001249315.25
First in ClinVar: May 12, 2020 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 4
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Pathogenic
(Sep 16, 2020)
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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: SCV001455816.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 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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Chronic visceral acid sphingomyelinase deficiency (Niemann-Pick disease type B) in 16 Polish patients: long-term follow-up. | Lipiński P | Orphanet journal of rare diseases | 2019 | PMID: 30795770 |
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 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
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 |
Identification of a 3' acceptor splice site mutation (g2610c) in the acid sphingomyelinase gene of patients with Niemann-Pick disease. | Levran O | Human molecular genetics | 1993 | PMID: 8499909 |
Human acid sphingomyelinase. Isolation, nucleotide sequence and expression of the full-length and alternatively spliced cDNAs. | Schuchman EH | The Journal of biological chemistry | 1991 | PMID: 1840600 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SMPD1 | - | - | - | - |
Text-mined citations for rs398123474 ...
HelpRecord last updated Oct 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.