For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed to segregate with biotin-responsive basal ganglia disease in multiple families (PMID: 15871139, 23742248, 27749535) and has also been observed in individuals with biotin-responsive basal ganglia disease (PMID: 24166474, 23742248). ClinVar contains an entry for this variant (Variation ID: 4563). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with alanine at codon 422 of the SLC19A3 protein (p.Thr422Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine.
ClinVar Genomic variation as it relates to human health
NM_025243.4(SLC19A3):c.1264A>G (p.Thr422Ala)
Germline
Classification
Help
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.
(12)
Help
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.
Pathogenic
12
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_025243.4(SLC19A3):c.1264A>G (p.Thr422Ala)
Variation ID: 4563 Accession: VCV000004563.44
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q36.3 2: 227688216 (GRCh38) [ NCBI UCSC ] 2: 228552932 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 May 22, 2017 Oct 20, 2024 Jul 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_025243.4:c.1264A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_079519.1:p.Thr422Ala missense NC_000002.12:g.227688216T>C NC_000002.11:g.228552932T>C NG_016359.1:g.34814A>G Q9BZV2:p.Thr422Ala - Protein change
- T422A
- Other names
- -
- Canonical SPDI
- NC_000002.12:227688215:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| SLC19A3 | - | - |
GRCh38 GRCh37 |
670 | 695 | |
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. |
|---|---|---|---|---|
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Oct 9, 2023 | RCV000004825.26 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2024 | RCV000489300.21 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 29, 2020 | RCV002512775.3 | |
|
Thiamine metabolism dysfunction syndrome 2 (biotin/thiamine-responsive basal ganglia disease type)
|
Pathogenic (1) |
criteria provided, single submitter
|
Mar 14, 2024 | RCV004527286.2 |
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
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Biotin-responsive basal ganglia disease
Affected status: yes
Allele origin:
germline
|
Pathology and Clinical Laboratory Medicine, King Fahad Medical City
Accession: SCV000996282.1
First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019 |
Number of individuals with the variant: 6
Ethnicity/Population group: Arab
Geographic origin: Middle East
|
|
|
Pathogenic
(Aug 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Biotin-responsive basal ganglia disease
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001426161.1
First in ClinVar: Aug 03, 2020 Last updated: Aug 03, 2020 |
|
|
|
Pathogenic
(Oct 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Biotin-responsive basal ganglia disease
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002020637.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jun 15, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Biotin-responsive basal ganglia disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001388713.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed to segregate with biotin-responsive basal ganglia disease in multiple families (PMID: 15871139, 23742248, 27749535) and has also been observed in individuals with biotin-responsive basal ganglia disease (PMID: 24166474, 23742248). ClinVar contains an entry for this variant (Variation ID: 4563). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with alanine at codon 422 of the SLC19A3 protein (p.Thr422Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. (less)
|
|
|
Pathogenic
(Mar 14, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Thiamine metabolism dysfunction syndrome 2 (biotin/thiamine-responsive basal ganglia disease type)
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV005038886.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
|
|
|
Pathogenic
(Dec 09, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Biotin-responsive basal ganglia disease
Affected status: unknown
Allele origin:
biparental
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000782560.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
|
|
|
Pathogenic
(Nov 15, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000577585.4
First in ClinVar: May 22, 2017 Last updated: May 22, 2017 |
Comment:
The T422A pathogenic variant in the SLC19A3 gene has been reported previously in association with biotin-responsive basal ganglia disease (BBGD) in multiple consanguineous families, and … (more)
The T422A pathogenic variant in the SLC19A3 gene has been reported previously in association with biotin-responsive basal ganglia disease (BBGD) in multiple consanguineous families, and has been described as a founder mutation in the Saudi population (Zeng et al., 2005; Distelmaier et al., 2014; Alfadhel et al., 2013). The T422A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T422A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T422A as a pathogenic variant. (less)
|
|
|
Pathogenic
(Nov 13, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Biotin-responsive basal ganglia disease
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001520854.1
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].
|
|
|
Pathogenic
(Dec 29, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003548802.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.1264A>G (p.T422A) alteration is located in exon 5 (coding exon 4) of the SLC19A3 gene. This alteration results from an A to G substitution … (more)
The c.1264A>G (p.T422A) alteration is located in exon 5 (coding exon 4) of the SLC19A3 gene. This alteration results from an A to G substitution at nucleotide position 1264, causing the threonine (T) at amino acid position 422 to be replaced by an alanine (A). Based on data from the Genome Aggregation Database (gnomAD), the SLC19A3 c.1264A>G alteration was not observed, with coverage at this position. This mutation has been identified in several Saudi Arabian individuals in the homozygous state with biotin-responsive basal ganglia disease (Zeng, 2005; Alfadhel, 2013; Distelmaier, 2014; Aljabri, 2016; Algahtani, 2017). The p.T422A alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
|
Pathogenic
(Jul 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500708.21
First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024 |
Comment:
SLC19A3: PP1:Strong, PM1, PM2, PM3, PP4
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Sep 26, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Biotin-responsive basal ganglia disease
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001133100.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
|
|
|
Pathogenic
(Nov 01, 2006)
|
no assertion criteria provided
Method: literature only
|
BIOTIN-THIAMINE-RESPONSIVE BASAL GANGLIA DISEASE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025001.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
In 3 families, all of Saudi origin, with biotin-thiamine-responsive basal ganglia disease (BTBGD; 607483), Zeng et al. (2005) identified an A-to-G transition at nucleotide position … (more)
In 3 families, all of Saudi origin, with biotin-thiamine-responsive basal ganglia disease (BTBGD; 607483), Zeng et al. (2005) identified an A-to-G transition at nucleotide position 1264 in exon 5 of the SLC19A3, predicted to result in a substitution of threonine at codon 422 to alanine (T422A). Eichler et al. (2017) reported a 20-year-old Saudi woman with BTBGD who was homozygous for the T422A mutation in the SLC19A3 gene. In canine kidney cells and human duodenal cells, both polarized epithelial cell lines, Subramanian et al. (2006) showed that the T422A mutant protein, which is in transmembrane domain 11, 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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Comment:
Comment:
The T422A pathogenic variant in the SLC19A3 gene has been reported previously in association with biotin-responsive basal ganglia disease (BBGD) in multiple consanguineous families, and has been described as a founder mutation in the Saudi population (Zeng et al., 2005; Distelmaier et al., 2014; Alfadhel et al., 2013). The T422A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T422A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T422A as a pathogenic variant.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
The c.1264A>G (p.T422A) alteration is located in exon 5 (coding exon 4) of the SLC19A3 gene. This alteration results from an A to G substitution at nucleotide position 1264, causing the threonine (T) at amino acid position 422 to be replaced by an alanine (A). Based on data from the Genome Aggregation Database (gnomAD), the SLC19A3 c.1264A>G alteration was not observed, with coverage at this position. This mutation has been identified in several Saudi Arabian individuals in the homozygous state with biotin-responsive basal ganglia disease (Zeng, 2005; Alfadhel, 2013; Distelmaier, 2014; Aljabri, 2016; Algahtani, 2017). The p.T422A alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
SLC19A3: PP1:Strong, PM1, PM2, PM3, PP4
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. |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed to segregate with biotin-responsive basal ganglia disease in multiple families (PMID: 15871139, 23742248, 27749535) and has also been observed in individuals with biotin-responsive basal ganglia disease (PMID: 24166474, 23742248). ClinVar contains an entry for this variant (Variation ID: 4563). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with alanine at codon 422 of the SLC19A3 protein (p.Thr422Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine.
Comment:
The T422A pathogenic variant in the SLC19A3 gene has been reported previously in association with biotin-responsive basal ganglia disease (BBGD) in multiple consanguineous families, and has been described as a founder mutation in the Saudi population (Zeng et al., 2005; Distelmaier et al., 2014; Alfadhel et al., 2013). The T422A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T422A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T422A as a pathogenic variant.
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
The c.1264A>G (p.T422A) alteration is located in exon 5 (coding exon 4) of the SLC19A3 gene. This alteration results from an A to G substitution at nucleotide position 1264, causing the threonine (T) at amino acid position 422 to be replaced by an alanine (A). Based on data from the Genome Aggregation Database (gnomAD), the SLC19A3 c.1264A>G alteration was not observed, with coverage at this position. This mutation has been identified in several Saudi Arabian individuals in the homozygous state with biotin-responsive basal ganglia disease (Zeng, 2005; Alfadhel, 2013; Distelmaier, 2014; Aljabri, 2016; Algahtani, 2017). The p.T422A alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
SLC19A3: PP1:Strong, PM1, PM2, PM3, PP4
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Case 38-2017. A 20-Year-Old Woman with Seizures and Progressive Dystonia. | Eichler FS | The New England journal of medicine | 2017 | PMID: 29236641 |
| Biotin-thiamine-responsive basal ganglia disease: catastrophic consequences of delay in diagnosis and treatment. | Algahtani H | Neurological research | 2017 | PMID: 27905264 |
| A case report of biotin-thiamine-responsive basal ganglia disease in a Saudi child: Is extended genetic family study recommended? | Aljabri MF | Medicine | 2016 | PMID: 27749535 |
| Biotin-responsive Basal Ganglia disease: a treatable differential diagnosis of leigh syndrome. | Distelmaier F | JIMD reports | 2014 | PMID: 24166474 |
| Biotin-responsive basal ganglia disease should be renamed biotin-thiamine-responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of 18 new cases. | Alfadhel M | Orphanet journal of rare diseases | 2013 | PMID: 23742248 |
| 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 rs121917884 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 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.