ClinVar Genomic variation as it relates to human health
NM_025243.4(SLC19A3):c.68G>T (p.Gly23Val)
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_025243.4(SLC19A3):c.68G>T (p.Gly23Val)
Variation ID: 4562 Accession: VCV000004562.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q36.3 2: 227702251 (GRCh38) [ NCBI UCSC ] 2: 228566967 (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 Apr 4, 2013 May 12, 2024 Dec 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_025243.4:c.68G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_079519.1:p.Gly23Val missense NM_001371412.1:c.68G>T NC_000002.12:g.227702251C>A NC_000002.11:g.228566967C>A NG_016359.1:g.20779G>T Q9BZV2:p.Gly23Val - Protein change
- G23V
- Other names
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- Canonical SPDI
- NC_000002.12:227702250:C: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 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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SLC19A3 | - | - |
GRCh38 GRCh37 |
653 | 678 |
Conditions - Germline
Condition
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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
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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 (8) |
criteria provided, multiple submitters, no conflicts
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Dec 18, 2023 | RCV000004824.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 1, 2020 | RCV001310775.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 18, 2023 | RCV003242961.3 |
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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Pathogenic
(Dec 18, 2017)
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criteria provided, single submitter
Method: clinical testing
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Biotin-responsive basal ganglia disease
Affected status: yes
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746892.2
First in ClinVar: Jun 20, 2017 Last updated: Dec 11, 2022 |
Age: 0-9 years
Sex: female
Geographic origin: Iran
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Likely pathogenic
(Nov 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Biotin-responsive basal ganglia disease
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003808035.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PS3 supporting, PM2 moderated, PM3 strong, PP1 supporting, PP3 supporting
Number of individuals with the variant: 1
Clinical Features:
Secondary Caesarian section (present) , Abnormal delivery (present) , Dysmetria (present) , Caesarian section (present) , Choreoathetosis (present) , Chorea (present) , Cerebellar ataxia (present) … (more)
Secondary Caesarian section (present) , Abnormal delivery (present) , Dysmetria (present) , Caesarian section (present) , Choreoathetosis (present) , Chorea (present) , Cerebellar ataxia (present) , Intellectual disability, mild (present) , Progressive choreoathetosis (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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Pathogenic
(Dec 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Biotin-responsive basal ganglia disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004242388.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
Criteria applied: PM3_VSTR,PM5,PM2_SUP,PP3
Clinical Features:
Thiamine-responsive megaloblastic anemia (present) , Global developmental delay (present) , Developmental regression (present)
Sex: female
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Pathogenic
(Dec 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Biotin-responsive basal ganglia disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001215332.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 23 of the SLC19A3 protein (p.Gly23Val). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 23 of the SLC19A3 protein (p.Gly23Val). This variant is present in population databases (rs121917882, gnomAD 0.0009%). This missense change has been observed in individuals with biotin-responsive basal ganglia disease (PMID: 15871139, 23589815, 26657515, 29101630). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4562). 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 SLC19A3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect SLC19A3 function (PMID: 16790503). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500710.18
First in ClinVar: Mar 14, 2021 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Mar 15, 2019)
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criteria provided, single submitter
Method: clinical testing
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Biotin-responsive basal ganglia disease
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369934.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2.
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Biotin-responsive basal ganglia disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004101498.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
The missense variant p.G23V in SLC19A3 (NM_025243.4) has been previosuly reported to segregate with biotin-responsive basal ganglia disease in families ( Zeng et al, 2005; … (more)
The missense variant p.G23V in SLC19A3 (NM_025243.4) has been previosuly reported to segregate with biotin-responsive basal ganglia disease in families ( Zeng et al, 2005; Pérez et al, 2013). This variant has been reported to affect SLC19A3 protein function (Subramanian et al, 2006). The p.G23V variant has a gnomAD frequency of 0.0003977 % and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between glycine and valine. The p.G23V missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.68 in SLC19A3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Generalized dystonia (present)
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Pathogenic
(Apr 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003941364.2
First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024 |
Comment:
The c.68G>T (p.G23V) alteration is located in exon 2 (coding exon 1) of the SLC19A3 gene. This alteration results from a G to T substitution … (more)
The c.68G>T (p.G23V) alteration is located in exon 2 (coding exon 1) of the SLC19A3 gene. This alteration results from a G to T substitution at nucleotide position 68, causing the glycine (G) at amino acid position 23 to be replaced by a valine (V). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was detected in the homozygous state, and in conjunction with another alteration in SLC19A3, in multiple individuals with SLC19A3-related thiamine metabolism dysfunction syndrome (Gowda, 2018; Tonduti, 2018; Pronicki, 2017; Whitford, 2017; Kevelam, 2013; Pérez-Dueñas, 2013; Zeng, 2005). This amino acid position is highly conserved in available vertebrate species. Functional assays show impaired thiamine accumulation compared to controls in vitro (Subramanian, 2006). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Mar 20, 2017)
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no assertion criteria provided
Method: research
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Biotin-responsive basal ganglia disease
Affected status: yes
Allele origin:
maternal
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Applied Translational Genetics Group, University of Auckland
Accession: SCV000574715.1
First in ClinVar: Jun 20, 2017 Last updated: Jun 20, 2017 |
Observation 1:
Family history: yes
Comment on evidence:
Segregates in classical compound heterozygous fashion with NC_000002.11:g.228582251_228587060del: Each parent carries only one variant and does not show the condition, while both children carry both … (more)
Segregates in classical compound heterozygous fashion with NC_000002.11:g.228582251_228587060del: Each parent carries only one variant and does not show the condition, while both children carry both variants and show the condition (less)
Secondary finding: no
Observation 2:
Family history: yes
Comment on evidence:
Segregates in classical compound heterozygous fashion with NC_000002.11:g.228582251_228587060del: Each parent carries only one variant and does not show the condition, while both children carry both … (more)
Segregates in classical compound heterozygous fashion with NC_000002.11:g.228582251_228587060del: Each parent carries only one variant and does not show the condition, while both children carry both variants and show the condition (less)
Secondary finding: no
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Pathogenic
(Nov 01, 2006)
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no assertion criteria provided
Method: literature only
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BIOTIN-THIAMINE-RESPONSIVE BASAL GANGLIA DISEASE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025000.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
In 2 patients with biotin-thiamine-responsive basal ganglia disease (BTBGD; 607483) in a Yemeni family, Zeng et al. (2005) found a homozygous G-to-T change at nucleotide … (more)
In 2 patients with biotin-thiamine-responsive basal ganglia disease (BTBGD; 607483) in a Yemeni family, Zeng et al. (2005) found a homozygous G-to-T change at nucleotide 68 in exon 2 of the SLC19A3 gene, which was predicted to alter a highly conserved glycine at codon 23 to valine (G23V). This mutation was predicted to alter the first transmembrane domain of the SLC19A3 protein. In canine kidney cells and human duodenal cells, both polarized epithelial cell lines, Subramanian et al. (2006) showed that the G23V mutant protein localized normally to the apical plasma membrane, similar to the wildtype protein, but showed decreased expression. However, cells expressing the mutant SLC19A3 protein had significantly impaired thiamine transport, similar to untransfected cells. (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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SLC19A3 related disorder: Treatment implication and clinical outcome of 2 new patients. | Tonduti D | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2018 | PMID: 29287834 |
Biotin Thiamin Responsive Basal Ganglia Disease in Siblings. | Gowda VK | Indian journal of pediatrics | 2018 | PMID: 29101630 |
Compound heterozygous SLC19A3 mutations further refine the critical promoter region for biotin-thiamine-responsive basal ganglia disease. | Whitford W | Cold Spring Harbor molecular case studies | 2017 | PMID: 28696212 |
Neuropathological characteristics of the brain in two patients with SLC19A3 mutations related to the biotin-thiamine-responsive basal ganglia disease. | Pronicki M | Folia neuropathologica | 2017 | PMID: 28677371 |
Free-thiamine is a potential biomarker of thiamine transporter-2 deficiency: a treatable cause of Leigh syndrome. | Ortigoza-Escobar JD | Brain : a journal of neurology | 2016 | PMID: 26657515 |
Reversible lactic acidosis in a newborn with thiamine transporter-2 deficiency. | Pérez-Dueñas B | Pediatrics | 2013 | PMID: 23589815 |
Exome sequencing reveals mutated SLC19A3 in patients with an early-infantile, lethal encephalopathy. | Kevelam SH | Brain : a journal of neurology | 2013 | PMID: 23482991 |
Biotin-responsive basal ganglia disease-linked mutations inhibit thiamine transport via hTHTR2: biotin is not a substrate for hTHTR2. | Subramanian VS | American journal of physiology. Cell physiology | 2006 | PMID: 16790503 |
Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. | Zeng WQ | American journal of human genetics | 2005 | PMID: 15871139 |
Text-mined citations for rs121917882 ...
HelpRecord last updated May 12, 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.