SLC19A3

Chr 2AR

solute carrier family 19 member 3

Also known as: BBGD, THMD2, THTR2, hTHTR2, thTr-2

NCBI Gene: 80704ENSG00000135917UniProt: Q9BZV2

This gene encodes a ubiquitously expressed transmembrane thiamine transporter that lacks folate transport activity. Mutations in this gene cause biotin-responsive basal ganglia disease (BBGD); a recessive disorder manifested in childhood that progresses to chronic encephalopathy, dystonia, quadriparesis, and death if untreated. Patients with BBGD have bilateral necrosis in the head of the caudate nucleus and in the putamen. Administration of high doses of biotin in the early progression of the disorder eliminates pathological symptoms while delayed treatment results in residual paraparesis, mild cognitive disability, or dystonia. Administration of thiamine is ineffective in the treatment of this disorder. Experiments have failed to show that this protein can transport biotin. Mutations in this gene also cause a Wernicke's-like encephalopathy.[provided by RefSeq, Jan 2010]

Primary Disease Associations & Inheritance

Thiamine metabolism dysfunction syndrome 2 (biotin/thiamine-responsive basal ganglia disease type)MIM #607483
AR
757
ClinVar variants
76
Pathogenic / LP
0.10
pLI score
0
Active trials
Clinical Summary— SLC19A3
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.
📋
ClinVar Variants
76 Pathogenic / Likely Pathogenic· 186 VUS of 757 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.59LOEUF
pLI 0.104
Z-score 2.82
OE 0.28 (0.14–0.59)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.37Z-score
OE missense 1.06 (0.96–1.17)
283 obs / 266.2 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.28 (0.14–0.59)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.06 (0.96–1.17)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.82
0≤1.21.6
LoF obs/exp: 5 / 17.8Missense obs/exp: 283 / 266.2Syn Z: 1.52

ClinVar Variant Classifications

757 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic48
Likely Pathogenic28
VUS186
Likely Benign194
Benign22
Conflicting16
48
Pathogenic
28
Likely Pathogenic
186
VUS
194
Likely Benign
22
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
4
31
0
48
Likely Pathogenic
9
10
9
0
28
VUS
3
154
29
0
186
Likely Benign
0
2
52
140
194
Benign
0
1
19
2
22
Conflicting
—16
Total25171140142494

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SLC19A3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SLC19A3-related thiamine metabolism dysfunction syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Thiamine metabolism dysfunction syndrome 2 (biotin/thiamine-responsive basal ganglia disease type)

MIM #607483

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Leigh Syndrome: A Study of 209 Patients at the Beijing Children's Hospital.
Stenton SL et al.·Ann Neurol
2022Cohort
SLC19A3 Gene Defects Sorting the Phenotype and Acronyms: Review.
Alfadhel M et al.·Neuropediatrics
2018Review
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.
Pronicka E et al.·J Transl Med
2016
SLC gene mutations and pediatric neurological disorders: diverse clinical phenotypes in a Saudi Arabian population.
Mir A et al.·Hum Genet
2022
Treatment of genetic defects of thiamine transport and metabolism.
Ortigoza-Escobar JD et al.·Expert Rev Neurother
2016Review
Rare Diseases Linked to Mutations in Vitamin Transporters Expressed in the Human Blood-Brain Barrier.
Yee SW et al.·Clin Pharmacol Ther
2024Review
Clinical profile and thiamine transporter gene (SLC19A2 and SLC19A3) variations in infants with thiamine-responsive pulmonary hypertension and acute respiratory infection.
Shenoy S et al.·J Trop Pediatr
2024
A wide spectrum of clinical and brain MRI findings in patients with SLC19A3 mutations.
Yamada K et al.·BMC Med Genet
2010Cohort
Emerging aspects of treatment in mitochondrial disorders.
Rahman S·J Inherit Metab Dis
2015Review
[Familial Wernicke's-like encephalopathy].
Miyajima H et al.·Rinsho Shinkeigaku
2010Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools