ClinVar Genomic variation as it relates to human health
NM_000543.5(SMPD1):c.1268A>G (p.His423Arg)
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.1268A>G (p.His423Arg)
Variation ID: 2136989 Accession: VCV002136989.3
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 6393621 (GRCh38) [ NCBI UCSC ] 11: 6414851 (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 Feb 8, 2023 Feb 28, 2024 Dec 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000543.5:c.1268A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000534.3:p.His423Arg missense NM_000543.4:c.1268A>G NM_001007593.3:c.1265A>G NP_001007594.2:p.His422Arg missense NM_001318087.2:c.1268A>G NP_001305016.1:p.His423Arg missense NM_001318088.2:c.347A>G NP_001305017.1:p.His116Arg missense NM_001365135.2:c.1136A>G NP_001352064.1:p.His379Arg missense NR_027400.3:n.1221A>G non-coding transcript variant NR_134502.2:n.740A>G non-coding transcript variant NC_000011.10:g.6393621A>G NC_000011.9:g.6414851A>G NG_011780.1:g.8197A>G NG_029615.1:g.30794T>C - Protein change
- H116R, H422R, H423R, H379R
- Other names
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- Canonical SPDI
- NC_000011.10:6393620:A:G
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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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- Links
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 |
964 | 1033 |
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 (1) |
criteria provided, single submitter
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Dec 20, 2023 | RCV003037365.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 3, 2023 | RCV003331417.1 |
Submissions - Germline
Classification
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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
(Aug 03, 2023)
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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: SCV004039185.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: SMPD1 c.1268A>G (p.His423Arg, it was also known as p.His421Arg in the literature) results in a non-conservative amino acid change located in the Calcineurin-like … (more)
Variant summary: SMPD1 c.1268A>G (p.His423Arg, it was also known as p.His421Arg in the literature) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type domain (IPR004843) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249054 control chromosomes (gnomAD). c.1268A>G has been reported in the literature in compound heterozygous individuals affected with Niemann-Pick Disease (McGovern_2006, Rodrguez-Pascau_2009, Aykut_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. In addition, another missense at the same codon, H423Y, has been classified as pathogenic in our lab. The following publications have been ascertained in the context of this evaluation (PMID: 23618813, 16434659, 19405096, 27725636). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Dec 20, 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: SCV003439784.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 423 of the SMPD1 protein (p.His423Arg). … (more)
This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 423 of the SMPD1 protein (p.His423Arg). This variant is present in population databases (rs767492080, gnomAD 0.0009%). This missense change has been observed in individual(s) with Niemann-Pick A disease (PMID: 16434659, 19405096). This variant is also known as H421R. ClinVar contains an entry for this variant (Variation ID: 2136989). 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%. This variant disrupts the p.His423 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12369017, 17876723, 27338287, 28600779). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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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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The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes. | Monies D | Human genetics | 2017 | PMID: 28600779 |
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 |
Analysis of the sphingomyelin phosphodiesterase 1 gene (SMPD1) in Turkish Niemann-Pick disease patients: mutation profile and description of a novel mutation. | Aykut A | Gene | 2013 | PMID: 23618813 |
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-deficient Niemann-Pick disease: novel findings in a Greek child. | Fotoulaki M | Journal of inherited metabolic disease | 2007 | PMID: 17876723 |
Natural history of Type A Niemann-Pick disease: possible endpoints for therapeutic trials. | McGovern MM | Neurology | 2006 | PMID: 16434659 |
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 |
Text-mined citations for this variant ...
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.