HLCS

holocarboxylase synthetase

Basic information

Region (hg38): 21:36748626-36990236

Links

ENSG00000159267 ∙ NCBI:3141 ∙ OMIM:609018 ∙ HGNC:4976 ∙ Uniprot:P50747 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• holocarboxylase synthetase deficiency (Definitive), mode of inheritance: AR
• holocarboxylase synthetase deficiency (Definitive), mode of inheritance: AR
• holocarboxylase synthetase deficiency (Strong), mode of inheritance: AR
• holocarboxylase synthetase deficiency (Supportive), mode of inheritance: AR
• holocarboxylase synthetase deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Holocarboxylase synthetase deficiency	AR	Biochemical	Biotin therapy can be beneficial to treat severe manifestations (which can include findings such as alopecia, keratoconjunctivitis, lactic acidosis, perioral erosions, and seizures), though the degree of response varies	Biochemical; Dermatologic; Neurologic; Ophthalmologic	6798072; 6794361; 6114319; 6790844; 6133032; 8319716; 7842009; 8817339; 9128289; 10190325; 11735028; 12124727; 12855220; 16134170; 16231399; 20095979; 21874615

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HLCS gene.

• Holocarboxylase synthetase deficiency (51 variants)
• not provided (6 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HLCS gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	316	3	320
missense	5	9	159	13	3	189
nonsense	25	30				55
start loss			1			1
frameshift	24	49	4			77
inframe indel			2			2
splice donor/acceptor (+/-2bp)	1	18	1			20
splice region		1	4	27	2	34
non coding			64	90	60	214
Total	55	106	232	419	66

Highest pathogenic variant AF is 0.0000263

Variants in HLCS

This is a list of pathogenic ClinVar variants found in the HLCS region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
21-36750993-G-A		Holocarboxylase synthetase deficiency	Uncertain significance (Jan 13, 2018)
21-36750999-T-C		Holocarboxylase synthetase deficiency	Likely benign (Jan 13, 2018)
21-36751019-CA-C		Holocarboxylase synthetase deficiency	Uncertain significance (Jun 14, 2016)
21-36751019-C-CA		Holocarboxylase synthetase deficiency	Uncertain significance (Jun 14, 2016)
21-36751037-G-A		Holocarboxylase synthetase deficiency	Uncertain significance (Jan 13, 2018)
21-36751071-T-C		Holocarboxylase synthetase deficiency	Uncertain significance (Jan 13, 2018)
21-36751083-CACTT-C		Holocarboxylase synthetase deficiency	Uncertain significance (Jun 14, 2016)
21-36751084-A-G		Holocarboxylase synthetase deficiency	Uncertain significance (Jan 13, 2018)
21-36751084-A-T		Holocarboxylase synthetase deficiency	Uncertain significance (Jan 12, 2018)
21-36751085-C-A		Holocarboxylase synthetase deficiency	Uncertain significance (Jan 13, 2018)
21-36751090-T-C		Holocarboxylase synthetase deficiency	Uncertain significance (Apr 27, 2017)
21-36751103-A-AAT		Holocarboxylase synthetase deficiency	Benign (Jun 14, 2016)
21-36751196-T-C		Holocarboxylase synthetase deficiency	Uncertain significance (Jan 12, 2018)
21-36751203-T-C		Holocarboxylase synthetase deficiency	Uncertain significance (Jan 12, 2018)
21-36751290-CAG-C		Holocarboxylase synthetase deficiency	Uncertain significance (Jun 14, 2016)
21-36751301-G-A		Holocarboxylase synthetase deficiency	Uncertain significance (Jan 13, 2018)
21-36751325-T-C		Holocarboxylase synthetase deficiency	Uncertain significance (Jan 12, 2018)
21-36751399-C-T		Holocarboxylase synthetase deficiency	Uncertain significance (Jan 12, 2018)
21-36751432-G-A		Holocarboxylase synthetase deficiency	Uncertain significance (Jan 13, 2018)
21-36751475-G-A		Holocarboxylase synthetase deficiency	Uncertain significance (Jan 12, 2018)
21-36751546-G-A		Holocarboxylase synthetase deficiency	Uncertain significance (Jan 12, 2018)
21-36751599-A-T		Holocarboxylase synthetase deficiency	Uncertain significance (Jan 13, 2018)
21-36751622-C-T		Holocarboxylase synthetase deficiency	Likely benign (Jan 12, 2018)
21-36751624-C-T		Holocarboxylase synthetase deficiency	Benign (Jan 12, 2018)
21-36751691-A-G		Holocarboxylase synthetase deficiency	Uncertain significance (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HLCS	protein_coding	protein_coding	ENST00000399120	9	239348

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.92e-8	0.966	125672	0	76	125748	0.000302

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.148	395	403	0.979	0.0000241	4746
Missense in Polyphen		120	135	0.88891		1585
Synonymous	-1.07	188	170	1.10	0.0000120	1458
Loss of Function	2.08	17	29.1	0.584	0.00000145	356

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000778	0.000778
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000762	0.000761
Finnish	0.00	0.00
European (Non-Finnish)	0.000300	0.000264
Middle Eastern	0.000762	0.000761
South Asian	0.000392	0.000294
Other	0.000489	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Post-translational modification of specific protein by attachment of biotin. Acts on various carboxylases such as acetyl- CoA-carboxylase, pyruvate carboxylase, propionyl CoA carboxylase, and 3-methylcrotonyl CoA carboxylase.
• Pathway: Biotin metabolism - Homo sapiens (human);Biotin Metabolism;Multiple carboxylase deficiency, neonatal or early onset form;Biotinidase Deficiency;Biotin transport and metabolism;Metabolism;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors;biotin-carboxyl carrier protein assembly (Consensus)

Recessive Scores

• pRec: 0.251

Intolerance Scores

• loftool: 0.0681
• rvis_EVS: -0.59
• rvis_percentile_EVS: 18.25

Haploinsufficiency Scores

• pHI: 0.0715
• hipred: N
• hipred_score: 0.417
• ghis: 0.551

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.998

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Hlcs

Gene ontology

• Biological process: biotin metabolic process;cell population proliferation;protein biotinylation;histone modification;response to biotin;histone biotinylation
• Cellular component: chromatin;nuclear lamina;mitochondrion;cytosol;nuclear matrix
• Molecular function: biotin-[acetyl-CoA-carboxylase] ligase activity;biotin-[methylcrotonoyl-CoA-carboxylase] ligase activity;biotin-[methylmalonyl-CoA-carboxytransferase] ligase activity;biotin-[propionyl-CoA-carboxylase (ATP-hydrolyzing)] ligase activity;protein binding;ATP binding;biotin binding;biotin-protein ligase activity;enzyme binding;protein homodimerization activity