ClinVar Genomic variation as it relates to human health
NM_000543.5(SMPD1):c.887G>A (p.Arg296Gln)
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.
Uncertain significance(1); Benign(6); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000543.5(SMPD1):c.887G>A (p.Arg296Gln)
Variation ID: 195091 Accession: VCV000195091.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 6391952 (GRCh38) [ NCBI UCSC ] 11: 6413182 (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 Jun 28, 2015 Oct 8, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000543.5:c.887G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000534.3:p.Arg296Gln missense NM_001007593.3:c.884G>A NP_001007594.2:p.Arg295Gln missense NM_001318087.2:c.887G>A NP_001305016.1:p.Arg296Gln missense NM_001318088.2:c.-75G>A 5 prime UTR NM_001365135.2:c.887G>A NP_001352064.1:p.Arg296Gln missense NR_027400.3:n.1012G>A non-coding transcript variant NC_000011.10:g.6391952G>A NC_000011.9:g.6413182G>A NG_011780.1:g.6528G>A - Protein change
- R296Q, R295Q
- Other names
- p.Arg296Gln
- Canonical SPDI
- NC_000011.10:6391951: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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0.01657 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00358
Exome Aggregation Consortium (ExAC) 0.00428
The Genome Aggregation Database (gnomAD) 0.01388
Trans-Omics for Precision Medicine (TOPMed) 0.01473
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01555
1000 Genomes Project 0.01657
1000 Genomes Project 30x 0.01780
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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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Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Jun 4, 2018 | RCV000175631.5 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jul 1, 2022 | RCV000224205.21 | |
Benign (2) |
criteria provided, single submitter
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Mar 6, 2018 | RCV000383492.7 | |
Benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV001081402.8 |
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
Help
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 benign
(Jun 04, 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: SCV000920242.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: SMPD1 c.887G>A (p.Arg296Gln) results in a conservative amino acid change located in the Calcineurin-like ApaH type phosphoesterase domain of the encoded protein sequence. … (more)
Variant summary: SMPD1 c.887G>A (p.Arg296Gln) results in a conservative amino acid change located in the Calcineurin-like ApaH type phosphoesterase domain of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0044 in 277234 control chromosomes in the gnomAD database, including 27 homozygotes. The observed variant frequency is approximately 1.96 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMPD1 causing Niemann-Pick Disease Type A phenotype (0.0022), strongly suggesting that the variant is benign. c.887G>A has been reported in the literature in individuals affected with Niemann-Pick Disease Type A. These report(s) do not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease Type A. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Benign
(May 06, 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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GeneDx
Accession: SCV001888861.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 15221801, 21228398, 20981092)
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Benign
(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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001116891.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 28, 2024 |
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Benign
(May 20, 2015)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000227155.5
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Number of individuals with the variant: 3
Sex: mixed
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Benign
(Mar 06, 2018)
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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: SCV000372934.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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Likely benign
(-)
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criteria provided, single submitter
Method: not provided
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005223219.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
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Benign
(Jul 01, 2022)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004135841.9
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
SMPD1: BP4, BS1, BS2
Number of individuals with the variant: 1
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Benign
(Aug 25, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000280601.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
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Uncertain significance
(Jan 03, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002541122.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
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Benign
(May 08, 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: SCV002092252.1
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 |
Carrier testing for severe childhood recessive diseases by next-generation sequencing. | Bell CJ | Science translational medicine | 2011 | PMID: 21228398 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SMPD1 | - | - | - | - |
Text-mined citations for rs35824453 ...
HelpRecord last updated Oct 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.