ClinVar Genomic variation as it relates to human health
NM_000543.5(SMPD1):c.1327C>T (p.Arg443Ter)
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.1327C>T (p.Arg443Ter)
Variation ID: 2993 Accession: VCV000002993.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 6393680 (GRCh38) [ NCBI UCSC ] 11: 6414910 (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 Feb 28, 2024 Dec 12, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000543.5:c.1327C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000534.3:p.Arg443Ter nonsense NM_001007593.3:c.1324C>T NP_001007594.2:p.Arg442Ter nonsense NM_001318087.2:c.1327C>T NP_001305016.1:p.Arg443Ter nonsense NM_001318088.2:c.406C>T NP_001305017.1:p.Arg136Ter nonsense NM_001365135.2:c.1195C>T NP_001352064.1:p.Arg399Ter nonsense NR_027400.3:n.1280C>T non-coding transcript variant NR_134502.2:n.799C>T non-coding transcript variant NC_000011.10:g.6393680C>T NC_000011.9:g.6414910C>T NG_011780.1:g.8256C>T NG_029615.1:g.30735G>A - Protein change
- R443*, R442*, R136*, R399*
- Other names
- R441*
- Canonical SPDI
- NC_000011.10:6393679:C: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00010
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
Help
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 |
970 | 1039 |
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 (2) |
criteria provided, single submitter
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- | RCV000003127.6 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Feb 8, 2022 | RCV000193674.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 25, 2023 | RCV000372224.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 12, 2023 | RCV000634567.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 19, 2018 | RCV000780732.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 22, 2020 | RCV001248934.4 |
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
(Jan 21, 2015)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type A
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000248992.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Feb 19, 2018)
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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: SCV000918242.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: SMPD1 c.1327C>T (p.Arg443X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: SMPD1 c.1327C>T (p.Arg443X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as pathogenic by our laboratory (c.1420_1421delCT (p.Leu474fsX20)). The variant allele was found at a frequency of 1.6e-05 in 243788 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in SMPD1 causing Niemann-Pick Disease (1.6e-05 vs 2.20e-03), allowing no conclusion about variant significance. The variant, c.1327C>T, has been reported in the literature in multiple individuals affected with Niemann-Pick Disease (Wasserstein_2006, Lee_SMPD1_2011, Mukherjee_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (Lee_2013). Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) classify the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(-)
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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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Baylor Genetics
Accession: SCV001163307.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
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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: SCV001422711.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Arg443Ter variant in SMPD1 (also known as p.Arg441Ter due to a difference in cDNA numbering) has been reported in at least 9 individuals with … (more)
The p.Arg443Ter variant in SMPD1 (also known as p.Arg441Ter due to a difference in cDNA numbering) has been reported in at least 9 individuals with Niemann-Pick disease (PMID: 22796693, 23415435, 8680412, 17011332, 19405096) and has been identified in 0.004% (4/111364) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs120074127). 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: 2993) as pathogenic by the University of Chicago, GeneDx, Counsyl, Invitae, Integrated Genetics, and OMIM. This nonsense variant leads to a premature termination codon at position 443, which is predicted to lead to a truncated or absent protein. Although this variant causes loss of function, it is pathogenic without the use of PVS1 and was used to establish whether loss of function is a mechanism of disease. The presence of this variant in 1 affected homozygote and in combination with reported pathogenic or likely pathogenic variants in at least 5 individuals with Niemann-Pick disease increases the likelihood that the p.Arg443Ter variant is pathogenic (VariationID: 93315, 93318, 198093; PMID: 19405096, 22796693, 23415435, 8680412, 17011332). The phenotype of individuals 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: 19405096, 22796693, 12607113, 23415435). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the presence of the variant in homozygotes and in trans with other pathogenic variants in affected individuals, the phenotype of patients with the variant being highly specific for disease, and the low frequency in the general population. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP4 (Richards 2015). (less)
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Pathogenic
(Feb 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type A
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581300.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PM3_STR, PS4_MOD, PM2_SUP
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Number of individuals with the variant: 2
Sex: female
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Pathogenic
(Jan 14, 2022)
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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: SCV002803793.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047822.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The stop gained variant c.1327C>T (p.Arg443Ter) in SMPD1 gene has been reported in individuals affected with Niemann-Pick disease type A and B (Mukherjee SB et.al.,2012). … (more)
The stop gained variant c.1327C>T (p.Arg443Ter) in SMPD1 gene has been reported in individuals affected with Niemann-Pick disease type A and B (Mukherjee SB et.al.,2012). This variant has been reported to the ClinVar database as Pathogenic. The c.1327C>T variant is reported with allele frequency 0.002% in gnomAD exomes and novel in 1000 Genomes. This variant is predicted to cause loss of normal protein function (Ricci V et.al.,2004). Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic . (less)
Clinical Features:
Hepatosplenomegaly (present) , Anemia (present) , Anemia (present)
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Pathogenic
(Dec 12, 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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Invitae
Accession: SCV000755897.7
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg443*) 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.Arg443*) 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 (rs120074127, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease type A and B (PMID: 8680412, 12607113, 17011332, 22796693). This variant is also known as 441X. ClinVar contains an entry for this variant (Variation ID: 2993). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 24, 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: SCV000486403.2
First in ClinVar: Oct 05, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Mar 25, 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: SCV000329525.5
First in ClinVar: Dec 06, 2016 Last updated: Apr 09, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay 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, 32292456, 26499107, 23770607, 12607113, 21502868, 26169295, 27338287, 22796693, 23415435, 19405096, 17011332, 8680412) (less)
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Pathogenic
(May 01, 2003)
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no assertion criteria provided
Method: literature only
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NIEMANN-PICK DISEASE, TYPE B
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023285.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 07, 2021 |
Comment on evidence:
Lee et al. (2003) studied a family in which a brother and sister were compound heterozygotes for the R608 deletion (607608.0002) and an arg441-to-ter (R441X) … (more)
Lee et al. (2003) studied a family in which a brother and sister were compound heterozygotes for the R608 deletion (607608.0002) and an arg441-to-ter (R441X) mutation in the SMPD1 gene. The proband, a 47-year-old man, had been admitted to a pediatric hospital at the age of 3 years for failure to thrive and hepatosplenomegaly. Patchy pulmonary infiltrates were found without obvious infectious cause, and splenectomy was performed. The diagnosis of type B Niemann-Pick disease (607616) was made on the basis of lipid-laden histiocytes on histopathology. Subsequent physical and neurologic development were normal and he worked as a mechanic. His sister, who was 2 years younger, was also diagnosed with type B Niemann-Pick disease on the basis of splenectomy. Her physical and intellectual development proceeded normally. At age 41 years, she was found to have severe coronary artery disease and underwent coronary artery bypass. Lee et al. (2003) concluded that compound heterozygosity for the 2 mutations was associated with low HDL cholesterol and premature coronary artery disease. (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: SCV002092269.1
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 |
Cholesterol trapping in Niemann-Pick disease type B fibroblasts can be relieved by expressing the phosphotyrosine binding domain of GULP. | Lee CY | Journal of clinical lipidology | 2013 | PMID: 23415435 |
Infant with type A Niemann Pick disease and undetectable Niemann Pick cells in bone marrow. | Mukherjee SB | Indian pediatrics | 2012 | PMID: 22796693 |
Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients. | Rodríguez-Pascau L | Human mutation | 2009 | PMID: 19405096 |
Acid sphingomyelinase deficiency: prevalence and characterization of an intermediate phenotype of Niemann-Pick disease. | Wasserstein MP | The Journal of pediatrics | 2006 | PMID: 17011332 |
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 |
Compound heterozygosity at the sphingomyelin phosphodiesterase-1 (SMPD1) gene is associated with low HDL cholesterol. | Lee CY | Human genetics | 2003 | PMID: 12607113 |
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 |
Two new mutations in the acid sphingomyelinase gene causing type a Niemann-pick disease: N389T and R441X. | Schuchman EH | Human mutation | 1995 | PMID: 8680412 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ab529f43-8a86-413f-8749-f8a4261ecb91 | - | - | - | - |
Text-mined citations for rs120074127 ...
HelpRecord last updated May 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.