ClinVar Genomic variation as it relates to human health
NM_012434.5(SLC17A5):c.116G>A (p.Arg39His)
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_012434.5(SLC17A5):c.116G>A (p.Arg39His)
Variation ID: 431079 Accession: VCV000431079.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q13 6: 73644582 (GRCh38) [ NCBI UCSC ] 6: 74354305 (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, 2017 Apr 6, 2024 Mar 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_012434.5:c.116G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_036566.1:p.Arg39His missense NC_000006.12:g.73644582C>T NC_000006.11:g.74354305C>T NG_008272.1:g.14433G>A - Protein change
- R39H
- Other names
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- Canonical SPDI
- NC_000006.12:73644581:C:T
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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) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 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
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
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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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SLC17A5 | - | - |
GRCh38 GRCh37 |
553 | 650 |
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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Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Mar 17, 2024 | RCV000496107.10 | |
Pathogenic (2) |
criteria provided, single submitter
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Nov 4, 2019 | RCV001332964.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 30, 2020 | RCV001548541.2 |
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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Likely pathogenic
(Nov 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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Salla disease
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000796029.1
First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017 |
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Pathogenic
(Nov 04, 2019)
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criteria provided, single submitter
Method: clinical testing
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Sialic acid storage disease, severe infantile type
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001525425.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Likely pathogenic
(Jun 30, 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: SCV001768469.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 31130284, 27848944, 29472023) (less)
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Likely pathogenic
(Sep 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Salla disease
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002027582.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Pathogenic
(Aug 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Salla disease
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004201219.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Salla disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003439472.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 39 of the SLC17A5 protein (p.Arg39His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 39 of the SLC17A5 protein (p.Arg39His). This variant is present in population databases (rs769235753, gnomAD 0.006%). This missense change has been observed in individual(s) with SLC17A5-related conditions (PMID: 27848944, 31130284, 34979677, 35322241). ClinVar contains an entry for this variant (Variation ID: 431079). 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 SLC17A5 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg39 amino acid residue in SLC17A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10581036, 10947946, 12794688, 15510212, 15516337, 18695252, 21781115). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Likely pathogenic
(Mar 17, 2024)
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criteria provided, single submitter
Method: research
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Salla disease
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804960.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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Likely pathogenic
(Oct 13, 2016)
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no assertion criteria provided
Method: clinical testing
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Salla disease
(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: SCV000586694.1
First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017 |
Comment:
This variant is not present in the 1000 Genomes database and has a minor allele frequency of less than 0.001% in the ExAC database. This … (more)
This variant is not present in the 1000 Genomes database and has a minor allele frequency of less than 0.001% in the ExAC database. This variant is predicted to be damaging by SIFT, LRT, PolyPhen and Mutation Taster. (less)
Clinical Features:
Leukodystrophy (present) , Neurodegeneration (present) , Abnormal facial shape (present)
Age: 10-19 years
Sex: male
Ethnicity/Population group: Hindu/Gujarati
Geographic origin: India
Method: DNA isolated from blood was used to perform targeted gene capture using a custom capture kit. The libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. The sequences obtained were aligned to human reference genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted gene relevant to clinical indication.
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Sialic acid storage disease, severe infantile type
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760186.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
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Likely pathogenic
(Mar 25, 2020)
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no assertion criteria provided
Method: clinical testing
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Salla disease
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002076737.1
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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Trio-based exome sequencing reveals a high rate of the de novo variants in intellectual disability. | Brea-Fernández AJ | European journal of human genetics : EJHG | 2022 | PMID: 35322241 |
Assessing Utility of Clinical Exome Sequencing in Diagnosis of Rare Idiopathic Neurodevelopmental Disorders in Indian Population. | Sheth H | Neurology India | 2021 | PMID: 34979677 |
Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. | Monies D | American journal of human genetics | 2019 | PMID: 31130284 |
Clinical exome sequencing: results from 2819 samples reflecting 1000 families. | Trujillano D | European journal of human genetics : EJHG | 2017 | PMID: 27848944 |
Functional characterization of vesicular excitatory amino acid transport by human sialin. | Miyaji T | Journal of neurochemistry | 2011 | PMID: 21781115 |
Identification of a vesicular aspartate transporter. | Miyaji T | Proceedings of the National Academy of Sciences of the United States of America | 2008 | PMID: 18695252 |
Varied mechanisms underlie the free sialic acid storage disorders. | Wreden CC | The Journal of biological chemistry | 2005 | PMID: 15516337 |
Functional characterization of wild-type and mutant human sialin. | Morin P | The EMBO journal | 2004 | PMID: 15510212 |
Biochemical and molecular analyses of infantile free sialic acid storage disease in North American children. | Kleta R | American journal of medical genetics. Part A | 2003 | PMID: 12794688 |
The spectrum of SLC17A5-gene mutations resulting in free sialic acid-storage diseases indicates some genotype-phenotype correlation. | Aula N | American journal of human genetics | 2000 | PMID: 10947946 |
A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases. | Verheijen FW | Nature genetics | 1999 | PMID: 10581036 |
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Text-mined citations for rs769235753 ...
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.