HLCS

Chr 21

holocarboxylase synthetase

Also known as: HCS

NCBI Gene: 3141ENSG00000159267UniProt: P50747

This gene encodes an enzyme that catalyzes the binding of biotin to carboxylases and histones. The protein plays an important role in gluconeogenesis, fatty acid synthesis and branched chain amino acid catabolism. Defects in this gene are the cause of holocarboxylase synthetase deficiency. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Jun 2011]

Primary Disease Associations & Inheritance

UniProtHolocarboxylase synthetase deficiency
589
ClinVar variants
138
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— HLCS
🧬
Gene-Disease Validity (ClinGen)
holocarboxylase synthetase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
138 Pathogenic / Likely Pathogenic· 234 VUS of 589 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.88LOEUF
pLI 0.000
Z-score 2.08
OE 0.58 (0.40–0.88)
Tolerant

Typical tolerance to LoF variation

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.
0.15Z-score
OE missense 0.98 (0.90–1.06)
395 obs / 403.4 exp
Tolerant

Mild missense constraint

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.0.58 (0.40–0.88)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.98 (0.90–1.06)
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.1.10
0≤1.21.6
LoF obs/exp: 17 / 29.1Missense obs/exp: 395 / 403.4Syn Z: -1.07

ClinVar Variant Classifications

589 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic61
Likely Pathogenic77
VUS234
Likely Benign202
Benign4
Conflicting11
61
Pathogenic
77
Likely Pathogenic
234
VUS
202
Likely Benign
4
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
21
0
40
0
61
Likely Pathogenic
51
6
20
0
77
VUS
1
189
37
7
234
Likely Benign
0
7
53
142
202
Benign
0
0
4
0
4
Conflicting
—11
Total73202154149589

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

View in ClinVar →

Protein Context — Lollipop Plot

HLCS · protein map & ClinVar variants

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

Gene2Phenotype Curations

HLCS-related holocarboxylase synthetase deficiency

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersSkin
G2P ↗

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — HLCS
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Biotin Homeostasis and Human Disorders: Recent Findings and Perspectives.
Karachaliou CE et al.·Int J Mol Sci
2024Review
Impaired glucose homeostasis and a novel HLCS pathogenic variant in holocarboxylase synthetase deficiency: a report of two cases and brief review.
Wu HR et al.·J Pediatr Endocrinol Metab
2020Review
Mutations in the holocarboxylase synthetase gene HLCS.
Suzuki Y et al.·Hum Mutat
2005Review
First-in-human clinical study of an embryonic stem cell product for urea cycle disorders.
Umezawa A et al.·Stem Cell Res Ther
2025
The Potential Clinical Use of Stem/Progenitor Cells and Organoids in Liver Diseases.
Nikokiraki C et al.·Cells
2022Review
Cell and cell-derivative-based therapy for liver diseases: current approaches and future promises.
Zahmatkesh E et al.·Expert Rev Gastroenterol Hepatol
2023Review
Clinical, biochemical, and genetic analysis of 28 Chinese patients with holocarboxylase synthetase deficiency.
Ling S et al.·Orphanet J Rare Dis
2023Cohort
Hepatocyte transplantation and advancements in alternative cell sources for liver-based regenerative medicine.
Lee CA et al.·J Mol Med (Berl)
2018Review
Multi-omics analysis of hiPSCs-derived HLCs matured on-chip revealed patterns typical of liver regeneration.
Danoy M et al.·Biotechnol Bioeng
2021
Emerging insights into mesenchymal stem cells and exosome-based therapies for liver injury.
Yang S et al.·Biomol Biomed
2025Review
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