ClinVar Genomic variation as it relates to human health
NM_000543.5(SMPD1):c.688C>T (p.Arg230Cys)
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.688C>T (p.Arg230Cys)
Variation ID: 370432 Accession: VCV000370432.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 6391753 (GRCh38) [ NCBI UCSC ] 11: 6412983 (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 Jan 6, 2017 Feb 28, 2024 Oct 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000543.5:c.688C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000534.3:p.Arg230Cys missense NM_001007593.3:c.685C>T NP_001007594.2:p.Arg229Cys missense NM_001318087.2:c.688C>T NP_001305016.1:p.Arg230Cys missense NM_001318088.2:c.-274C>T 5 prime UTR NM_001365135.2:c.688C>T NP_001352064.1:p.Arg230Cys missense NR_027400.3:n.813C>T non-coding transcript variant NC_000011.10:g.6391753C>T NC_000011.9:g.6412983C>T NG_011780.1:g.6329C>T - Protein change
- R230C, R229C
- Other names
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- Canonical SPDI
- NC_000011.10:6391752:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Unknown function
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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) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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 |
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
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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 (3) |
criteria provided, multiple submitters, no conflicts
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Jun 15, 2023 | RCV000409293.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 29, 2023 | RCV001229670.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 22, 2020 | RCV001248876.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 7, 2020 | RCV002223835.1 |
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 08, 2021)
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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 (Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001622390.1
First in ClinVar: May 20, 2021 Last updated: May 20, 2021 |
Comment:
A homozygous missense variant in exon 2 of the SMPD1 gene that results in the amino acid substitution of Cysteine for Arginine at codon 230 … (more)
A homozygous missense variant in exon 2 of the SMPD1 gene that results in the amino acid substitution of Cysteine for Arginine at codon 230 was detected. The observed variant c.688C>T (p.Arg230Cys) has not been reported in the 1000 genomes and gnomAD databases. The variant is reported in ClinVar as a pathogenic variant (ID 357985). The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. (less)
Clinical Features:
Hepatosplenomegaly (present)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Muslim
Geographic origin: India
Method: DNA extracted from blood was used to perform targeted gene capture using a custom smMIP panel. The libraries were sequenced to mean >100-300X coverage on the Illumina MiSeq sequencing platform. The sequences obtained are aligned to the human reference genome (GRCh37) using the BWA program and analyzed using Picard and GATK version 4.1.2 to identify variants relevant to the clinical indication.
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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: SCV001422551.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Arg230Cys variant in SMPD1 (also known as p.Arg228Cys due to a difference in cDNA numbering) has been reported in at least 7 individuals with … (more)
The p.Arg230Cys variant in SMPD1 (also known as p.Arg228Cys due to a difference in cDNA numbering) has been reported in at least 7 individuals with Niemann-Pick disease (PMID: 17011332, 22818240, 23356216, 23356216, 23252888, 19405096) and has been identified in 0.001% (1/111638) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs989639224). 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: 370432) as likely pathogenic by Counsyl. In vitro functional studies provide some evidence that the p.Arg230Cys variant may impact protein function (PMID: 19405096). However, these types of assays may not accurately represent biological function. 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 4 affected homozygotes increases the likelihood that the p.Arg230Cys variant is pathogenic (PMID: 17011332, 22818240, 23356216, 19405096). 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: 23252888, 22818240, 19405096, 23356216). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on in vitro studies and low prevalence in the general population. ACMG/AMP Criteria applied: PS3, PM2, PM3, PP3, PP4 (Richards 2015). (less)
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Likely pathogenic
(Jun 07, 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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502706.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: yes
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Likely pathogenic
(Feb 09, 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: SCV000485757.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Jun 15, 2023)
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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: SCV004203233.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Oct 29, 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: SCV001402124.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 230 of the SMPD1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 230 of the SMPD1 protein (p.Arg230Cys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with acid sphingomyelinase (ASM) deficiency (PMID: 17011332, 19405096, 22818240, 27338287). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg228Cys. ClinVar contains an entry for this variant (Variation ID: 370432). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 19405096). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 19, 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: SCV002091690.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Unknown function
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001622390.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Spectrum of SMPD1 mutations in Asian-Indian patients with acid sphingomyelinase (ASM)-deficient Niemann-Pick disease. | Ranganath P | American journal of medical genetics. Part A | 2016 | PMID: 27338287 |
Identification of a distinct mutation spectrum in the SMPD1 gene of Chinese patients with acid sphingomyelinase-deficient Niemann-Pick disease. | Zhang H | Orphanet journal of rare diseases | 2013 | PMID: 23356216 |
Identification of seven novel SMPD1 mutations causing Niemann-Pick disease types A and B. | Irun P | Clinical genetics | 2013 | PMID: 23252888 |
Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium: disease spectrum and natural course in attenuated patients. | Hollak CE | Molecular genetics and metabolism | 2012 | PMID: 22818240 |
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 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/44534cd2-84cf-4549-b7c5-f363be9153b8 | - | - | - | - |
Text-mined citations for rs989639224 ...
HelpRecord last updated Apr 06, 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.