ClinVar Genomic variation as it relates to human health
NM_000543.5(SMPD1):c.872G>A (p.Arg291His)
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.872G>A (p.Arg291His)
Variation ID: 195085 Accession: VCV000195085.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 6391937 (GRCh38) [ NCBI UCSC ] 11: 6413167 (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 Aug 5, 2018 Oct 13, 2024 Sep 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000543.5:c.872G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000534.3:p.Arg291His missense NM_001007593.3:c.869G>A NP_001007594.2:p.Arg290His missense NM_001318087.2:c.872G>A NP_001305016.1:p.Arg291His missense NM_001318088.2:c.-90G>A 5 prime UTR NM_001365135.2:c.872G>A NP_001352064.1:p.Arg291His missense NR_027400.3:n.997G>A non-coding transcript variant NC_000011.10:g.6391937G>A NC_000011.9:g.6413167G>A NG_011780.1:g.6513G>A - Protein change
- R291H, R290H
- Other names
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- Canonical SPDI
- NC_000011.10:6391936: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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00140
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00169
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 |
991 | 1060 |
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
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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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Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
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Sep 27, 2024 | RCV000675394.16 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 6, 2022 | RCV000694381.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 7, 2023 | RCV000780734.3 | |
Uncertain significance (3) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001004581.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 22, 2020 | RCV001248929.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 21, 2021 | RCV002516684.2 | |
SMPD1-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Nov 1, 2023 | RCV003917628.3 |
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
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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Uncertain significance
(Feb 20, 2018)
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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: SCV000227144.5
First in ClinVar: Jun 29, 2015 Last updated: Aug 05, 2018 |
Number of individuals with the variant: 10
Sex: mixed
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Uncertain significance
(Oct 31, 2018)
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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: SCV000894646.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(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: SCV001422703.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Arg291His variant in SMPD1 (also known as p.Arg289His due to a difference in cDNA numbering) has been reported in at least 5 individuals with … (more)
The p.Arg291His variant in SMPD1 (also known as p.Arg289His due to a difference in cDNA numbering) has been reported in at least 5 individuals with Niemann-Pick disease (PMID: 29555840, 15877209, 12369017, 12369017, 20111001, 30795770) and has been identified in 0.223% (288/129142) of European (non-Finnish) chromosomes, 0.076% (19/24968) of African chromosomes, and 0.020% (5/25108) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1803161). 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 at least 1 affected homozygote and in combination with reported pathogenic or likely pathogenic variants in 2 individuals with Niemann-Pick disease increases the likelihood that the p.Arg291His variant is pathogenic (VariationID: 2994, 550112; PMID: 29555840, 20111001, 15877209). In summary, the clinical significance of the p.Arg291His variant is uncertain. ACMG/AMP Criteria applied: BS1, PM3, PP3 (Richards 2015). (less)
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Uncertain significance
(Sep 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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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004099165.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
PS3_Supporting, PM3_Supporting, PP1, PP3
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Uncertain significance
(Oct 28, 2021)
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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: SCV003822016.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Dec 07, 2023)
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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: SCV000918244.3
First in ClinVar: Jun 03, 2019 Last updated: Feb 04, 2024 |
Comment:
Variant summary: SMPD1 c.872G>A (p.Arg291His) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type of the encoded protein sequence. … (more)
Variant summary: SMPD1 c.872G>A (p.Arg291His) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 251420 control chromosomes, predominantly at a frequency of 0.0022 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is similar to the expected frequency for a pathogenic variant in SMPD1 causing Niemann-Pick disease type B (0.0022 vs 0.0022), allowing no conclusion about variant significance. c.872G>A has been reported in the literature in individuals affected with Niemann-Pick disease type B and Parkinsons disease (Alcalay_2019, Kirkegaard_2010, Pavlu-Pereira_2005, Reunert_2016, Simonaro_2002, Zampieri_2015, Lipinski_2019). Due to the relatively high frequency of this variant in controls, interpretation of its presence in patients is unclear. Fibroblasts from patients with this variant along with a pathogenic variant had ASM enzyme activity which varied between 10-50% of wild-type (Pavlu-Pereira_2005, Kirkegaard_2010), however the variant was not tested in isolation. The following publications have been ascertained in the context of this evaluation (PMID: 30788890, 28590786, 20111001, 30795770, 15877209, 26981555, 12369017, 26499107). All the 11 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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Uncertain significance
(Oct 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003685997.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.872G>A (p.R291H) alteration is located in exon 2 (coding exon 2) of the SMPD1 gene. This alteration results from a G to A substitution … (more)
The c.872G>A (p.R291H) alteration is located in exon 2 (coding exon 2) of the SMPD1 gene. This alteration results from a G to A substitution at nucleotide position 872, causing the arginine (R) at amino acid position 291 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Apr 27, 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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Illumina Laboratory Services, Illumina
Accession: SCV001261320.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Jul 06, 2022)
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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
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000822824.3
First in ClinVar: Oct 10, 2018 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 291 of the SMPD1 protein (p.Arg291His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 291 of the SMPD1 protein (p.Arg291His). This variant is present in population databases (rs1803161, gnomAD 0.2%). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 12369017, 26499107, 30795770). This variant is also known as R289H. ClinVar contains an entry for this variant (Variation ID: 195085). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Sep 27, 2024)
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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: SCV001765011.2
First in ClinVar: Aug 07, 2021 Last updated: Oct 13, 2024 |
Comment:
Identified in patients with Niemann-Pick type B who had significant residual enzyme activity, who were also heterozygous for a second variant in SMPD1; the phase … (more)
Identified in patients with Niemann-Pick type B who had significant residual enzyme activity, who were also heterozygous for a second variant in SMPD1; the phase of these variants was not reported (PMID: 12369017, 15877209, 26499107, 30795770); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20111001, 15877209, 28590786, 26981555, 30788890, 29140481, 26499107, 30795770, 34426522, 38866761, 38153678, 38992987, 12369017) (less)
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Uncertain significance
(Feb 21, 2018)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000801064.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(Dec 03, 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: SCV002092250.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Uncertain significance
(Nov 01, 2023)
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no assertion criteria provided
Method: clinical testing
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SMPD1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004734116.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The SMPD1 c.872G>A variant is predicted to result in the amino acid substitution p.Arg291His. This variant has been documented in the compound heterozygous state in … (more)
The SMPD1 c.872G>A variant is predicted to result in the amino acid substitution p.Arg291His. This variant has been documented in the compound heterozygous state in at least two individuals thought to have Niemann-Pick disease; however in one case the second variant is of uncertain significance (Zampieri et al. 2016. PubMed ID: 26499107) and in the additional case(s) full genotype information was not provided (Simonaro et al. 2002. PubMed ID: 12369017, reported as R289H). This variant along with a second missense variant in this gene was also reported in one boy with Niemann-Pick disease, he also carried a homozygous 24bp duplication in CHIT1 gene (Reported as p.Arg289His in Table 1, Lipiński. 2019. PubMed ID: 30795770). This variant was also reported in one individual with Parkinson’s disease (Table S3, Robak. 2017. PubMed ID: 29140481). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549265.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The SMPD1 p.Arg291His variant was identified in 4 of 558 proband chromosomes (frequency: 0.0072) from individuals or families with Niemann-Pick Disease type B (Simonaro_2002_PMID:12369017; Pavlů-Pereira_2005_PMID:15877209; … (more)
The SMPD1 p.Arg291His variant was identified in 4 of 558 proband chromosomes (frequency: 0.0072) from individuals or families with Niemann-Pick Disease type B (Simonaro_2002_PMID:12369017; Pavlů-Pereira_2005_PMID:15877209; Reunert_2015_PMID:26981555; Zampieri_2016_PMID:26499107). The variant was identified in dbSNP (ID: rs1803161) and ClinVar (classified as uncertain significance by Invitae, EGL Genetics, Fulgent Genetics, Integrated Genetics and Mayo Clinic Genetic Testing). The variant was identified in control databases in 325 of 282810 chromosomes at a frequency of 0.001149 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 288 of 129142 chromosomes (freq: 0.00223), Other in 7 of 7224 chromosomes (freq: 0.000969), African in 19 of 24968 chromosomes (freq: 0.000761), European (Finnish) in 5 of 25108 chromosomes (freq: 0.000199), Latino in 5 of 35434 chromosomes (freq: 0.000141) and Ashkenazi Jewish in 1 of 10366 chromosomes (freq: 0.000096), but was not observed in the East Asian or South Asian populations. The p.Arg291 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Pathogenic
(-)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Niemann-Pick disease, type A
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163669.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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 mutations, activity, and α-synuclein accumulation in Parkinson's disease. | Alcalay RN | Movement disorders : official journal of the Movement Disorder Society | 2019 | PMID: 30788890 |
Contribution of tandem mass spectrometry to the diagnosis of lysosomal storage disorders. | Piraud M | Journal of inherited metabolic disease | 2018 | PMID: 29556840 |
Liver Fibrosis Associated With Crigler-Najjar Syndrome in a Compound Heterozygote: A Case Report. | Fata CR | Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society | 2017 | PMID: 28590786 |
Quantitation of plasmatic lysosphingomyelin and lysosphingomyelin-509 for differential screening of Niemann-Pick A/B and C diseases. | Kuchar L | Analytical biochemistry | 2017 | PMID: 28259515 |
SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants. | Zampieri S | Human mutation | 2016 | PMID: 26499107 |
Rapid Diagnosis of 83 Patients with Niemann Pick Type C Disease and Related Cholesterol Transport Disorders by Cholestantriol Screening. | Reunert J | EBioMedicine | 2015 | PMID: 26981555 |
Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology. | Kirkegaard T | Nature | 2010 | PMID: 20111001 |
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 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SMPD1 | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/dab49875-3ee7-4596-99f0-de0733487b40 | - | - | - | - |
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Text-mined citations for rs1803161 ...
HelpRecord last updated Oct 13, 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.