ClinVar Genomic variation as it relates to human health
NM_000543.5(SMPD1):c.538_539del (p.Leu180fs)
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.538_539del (p.Leu180fs)
Variation ID: 189096 Accession: VCV000189096.16
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 11p15.4 11: 6391602-6391603 (GRCh38) [ NCBI UCSC ] 11: 6412832-6412833 (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 Apr 4, 2013 Jun 17, 2024 Mar 12, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000543.5:c.538_539del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000534.3:p.Leu180fs frameshift NM_000543.4:c.538_539del NM_001007593.3:c.535_536del NP_001007594.2:p.Leu179fs frameshift NM_001318087.2:c.538_539del NP_001305016.1:p.Leu180fs frameshift NM_001318088.2:c.-424_-423del 5 prime UTR NM_001365135.2:c.538_539del NP_001352064.1:p.Leu180fs frameshift NR_027400.3:n.663_664del non-coding transcript variant NC_000011.10:g.6391603_6391604del NC_000011.9:g.6412833_6412834del NG_011780.1:g.6179_6180del - Protein change
- L179fs, L180fs
- Other names
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- Canonical SPDI
- NC_000011.10:6391601:TTT: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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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
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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 (5) |
criteria provided, multiple submitters, no conflicts
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Mar 12, 2024 | RCV000169504.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 14, 2023 | RCV001067762.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 22, 2020 | RCV001248975.3 |
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
(May 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:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697416.1
First in ClinVar: Mar 29, 2015 Last updated: Mar 29, 2015 |
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Likely pathogenic
(Dec 18, 2014)
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criteria provided, single submitter
Method: literature only
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Niemann-Pick disease, type A
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220967.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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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: SCV001422816.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Leu180AlafsTer12 variant in SMPD1 (also known as p.Leu178AlafsTer12 due to a difference in cDNA numbering) has been reported in at least 2 individuals with … (more)
The p.Leu180AlafsTer12 variant in SMPD1 (also known as p.Leu178AlafsTer12 due to a difference in cDNA numbering) has been reported in at least 2 individuals with Niemann-Pick disease (PMID: 15877209, 1618760) and has been identified in 0.003% (4/117524) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs786204694). 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 been reported in ClinVar (VariationID: 189096) as likely pathogenic by Counsyl and as pathogenic by Integrated Genetics. In vitro functional studies provide some evidence that the p.Leu180AlafsTer12 variant may impact protein function (PMID: 26499107, 1618760). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 180 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SMPD1 gene is a moderately established disease mechanism in autosomal recessive Niemann-Pick disease. The presence of this variant in 1 affected homozygote and in combination with a reported pathogenic variant in an individual with Niemann-Pick disease increases the likelihood that the p.Leu180AlafsTer12 variant is pathogenic (VariationID: 2896; PMID: 15877209). The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 1618760, 15877209). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the prediction that it causes loss of function, functional studies, and the presence of the variant in an affected homozygote and compound heterozygote. ACMG/AMP Criteria applied: PVS1, PS3, PM2, PM3, PP4 (Richards 2015). (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: SCV001232841.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu180Alafs*12) 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.Leu180Alafs*12) 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 present in population databases (rs746454813, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of acid sphingomyelinase deficiency (PMID: 1618760). This variant is also known as fsL178. ClinVar contains an entry for this variant (Variation ID: 189096). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 12, 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: SCV004203224.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Jan 01, 1992)
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no assertion criteria provided
Method: literature only
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NIEMANN-PICK DISEASE, TYPE A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023277.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Takahashi et al. (1992) found that a type A Niemann-Pick disease (257200) patient of European ancestry was heteroallelic for a 2-base (TT) deletion in exon … (more)
Takahashi et al. (1992) found that a type A Niemann-Pick disease (257200) patient of European ancestry was heteroallelic for a 2-base (TT) deletion in exon 2, which caused a frameshift mutation at SMPD1 codon 178, leading to a premature stop at codon 190. The mutation on the other chromosome was a G-to-A transition in exon 3 which caused a methionine-to-isoleucine substitution at codon 382 (M382I). (less)
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Pathogenic
(Mar 17, 2017)
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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: SCV002091682.1
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 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 |
Acid sphingomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty-five Czech and Slovak patients. A multi-approach study. | Pavlů-Pereira H | Journal of inherited metabolic disease | 2005 | PMID: 15877209 |
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 and expression of five mutations in the human acid sphingomyelinase gene causing types A and B Niemann-Pick disease. Molecular evidence for genetic heterogeneity in the neuronopathic and non-neuronopathic forms. | Takahashi T | The Journal of biological chemistry | 1992 | PMID: 1618760 |
Identification of a missense mutation (S436R) in the acid sphingomyelinase gene from a Japanese patient with type B Niemann-Pick disease. | Takahashi T | Human mutation | 1992 | PMID: 1301192 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/698af9c3-c4b7-48e0-9357-c544a15221de | - | - | - | - |
Text-mined citations for rs786204694 ...
HelpRecord last updated Sep 29, 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.