ClinVar Genomic variation as it relates to human health
NM_000543.5(SMPD1):c.1805G>A (p.Arg602His)
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.1805G>A (p.Arg602His)
Variation ID: 188955 Accession: VCV000188955.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 6394516 (GRCh38) [ NCBI UCSC ] 11: 6415746 (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 Mar 29, 2015 Jun 17, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000543.5:c.1805G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000534.3:p.Arg602His missense NM_001007593.3:c.1802G>A NP_001007594.2:p.Arg601His missense NM_001318087.2:c.*298G>A 3 prime UTR NM_001318088.2:c.884G>A NP_001305017.1:p.Arg295His missense NM_001365135.2:c.1673G>A NP_001352064.1:p.Arg558His missense NR_027400.3:n.1758G>A non-coding transcript variant NR_134502.2:n.1297G>A non-coding transcript variant NC_000011.10:g.6394516G>A NC_000011.9:g.6415746G>A NG_011780.1:g.9092G>A NG_029615.1:g.29899C>T - Protein change
- R602H, R558H, R295H, R601H
- Other names
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- Canonical SPDI
- NC_000011.10:6394515: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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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 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
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 |
985 | 1054 |
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 (3) |
criteria provided, multiple submitters, no conflicts
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Jan 16, 2024 | RCV000169329.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV001208506.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 14, 2022 | RCV001248877.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 16, 2019 | RCV001781526.4 |
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
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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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Likely pathogenic
(Sep 02, 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: SCV000220664.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Jan 16, 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: SCV004203215.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Jan 23, 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: SCV001422553.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Arg602His variant in SMPD1 (also known as p.Arg600His due to a difference in cDNA numbering) has been reported in at least 6 individuals with … (more)
The p.Arg602His variant in SMPD1 (also known as p.Arg600His due to a difference in cDNA numbering) has been reported in at least 6 individuals with Niemann-Pick disease (PMID: 15545621, 15234149, 12712061, 26499107, 15241805) and has been identified in 0.012% (2/16240 of African chromosomes, 0.003% (1/34580) of Latino chromosomes, and 0.001% (1/113576) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP 188955). 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: 188955) as likely pathogenic by Counsyl. In vitro functional studies provide some evidence that the p.Arg602His variant may impact protein function (PMID: 16010684, 21098024). 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 an affected homozygote and in combination with a reported pathogenic variants in 3 individuals with Niemann-Pick disease increases the likelihood that the p.Arg602Pro variant is pathogenic (VariationID: 198093, 188840; PMID: 15545621, 15234149, 12712061, 15241805). One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg602Pro, has been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 16010684, 21098024, 15241805, 27725636). The p.Arg602His variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 21098024, 27725636). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on its presence in affected homozygotes and compound heterozygotes in trans with pathogenic variants, in vitro functional studies, the presence of other variants at the same residue, and the functional importance of the region it falls in. ACMG/AMP Criteria applied: PM3_strong, PS3_moderate, PM5, PM2_supporting, PP3, PM1_supporting (Richards 2015). (less)
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Pathogenic
(Apr 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Sphingomyelin/cholesterol lipidosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511550.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: SMPD1 c.1805G>A (p.Arg602His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: SMPD1 c.1805G>A (p.Arg602His) results in a non-conservative amino acid change in 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 1.6e-05 in 249502 control chromosomes (gnomAD). c.1805G>A has been reported in the literature in multiple individuals affected with Niemann-Pick Disease (e.g. Wasserstein_2004, Zampieri_2016, Hu_2021). 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 13% of normal enzymatic activity (Dardis_2005, Zampieri_2016). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 16, 2019)
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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: SCV002020761.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 31, 2024)
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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: SCV001379897.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 602 of the SMPD1 protein (p.Arg602His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 602 of the SMPD1 protein (p.Arg602His). This variant is present in population databases (rs370129081, gnomAD 0.01%). This missense change has been observed in individuals with Niemann-Pick disease (PMID: 12712061, 15241805, 27338287). This variant is also known as R600H. ClinVar contains an entry for this variant (Variation ID: 188955). 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: 16010684, 21098024). This variant disrupts the p.Arg602 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 15241805), which suggests that this may be a clinically significant amino acid residue. 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: SCV002092300.1
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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Clinical, biochemical, and genotype-phenotype correlations of 118 patients with Niemann-Pick disease Types A/B. | Hu J | Human mutation | 2021 | PMID: 33675270 |
Human acid sphingomyelinase structures provide insight to molecular basis of Niemann-Pick disease. | Zhou YF | Nature communications | 2016 | PMID: 27725636 |
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 |
SMPD1 Mutation Update: Database and Comprehensive Analysis of Published and Novel Variants. | Zampieri S | Human mutation | 2016 | PMID: 26499107 |
A novel mechanism of lysosomal acid sphingomyelinase maturation: requirement for carboxyl-terminal proteolytic processing. | Jenkins RW | The Journal of biological chemistry | 2011 | PMID: 21098024 |
Carboxyl-terminal disulfide bond of acid sphingomyelinase is critical for its secretion and enzymatic function. | Lee CY | Biochemistry | 2007 | PMID: 18052040 |
Functional in vitro characterization of 14 SMPD1 mutations identified in Italian patients affected by Niemann Pick Type B disease. | Dardis A | Human mutation | 2005 | PMID: 16010684 |
The natural history of type B Niemann-Pick disease: results from a 10-year longitudinal study. | Wasserstein MP | Pediatrics | 2004 | PMID: 15545621 |
Acid sphingomyelinase: identification of nine novel mutations among Italian Niemann Pick type B patients and characterization of in vivo functional in-frame start codon. | Pittis MG | Human mutation | 2004 | PMID: 15241805 |
Ocular manifestations of Niemann-Pick disease type B. | McGovern MM | Ophthalmology | 2004 | PMID: 15234149 |
Growth restriction in children with type B Niemann-Pick disease. | Wasserstein MP | The Journal of pediatrics | 2003 | PMID: 12712061 |
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/415b1409-8c06-497e-994b-b3c78deeb18b | - | - | - | - |
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Text-mined citations for rs370129081 ...
HelpRecord last updated Jun 17, 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.