LIAS

lipoic acid synthetase, the group of Radical S-adenosylmethionine domain containing

Basic information

Region (hg38): 4:39459004-39485109

Links

ENSG00000121897 ∙ NCBI:11019 ∙ OMIM:607031 ∙ HGNC:16429 ∙ Uniprot:O43766 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• lipoic acid synthetase deficiency (Strong), mode of inheritance: AR
• lipoic acid synthetase deficiency (Moderate), mode of inheritance: AR
• lipoic acid synthetase deficiency (Strong), mode of inheritance: AR
• lipoic acid synthetase deficiency (Supportive), mode of inheritance: AR
• lipoic acid synthetase deficiency (Strong), mode of inheritance: AR
• Leigh syndrome (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hyperglycinemia, lactic acidosis, and seizures	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Biochemical; Neurologic	22152680; 24334290; 36680912

ClinVar

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

• Lipoic_acid_synthetase_deficiency (350 variants)
• not_provided (68 variants)
• Inborn_genetic_diseases (36 variants)
• LIAS-related_disorder (7 variants)
• not_specified (7 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LIAS gene is commonly pathogenic or not. These statistics are base on transcript: NM_000006859.4. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	71		72
missense	1	6	169	5		181
nonsense	5	2	2			9
start loss			1			1
frameshift	13	3		1		17
splice donor/acceptor (+/-2bp)		4	3			7
Total	19	15	176	77	0

Highest pathogenic variant AF is 0.000021189398

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LIAS	protein_coding	protein_coding	ENST00000261434	11	18654

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		125715	0	30	125745	0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.25	153	203	0.753	0.0000106	2406
Missense in Polyphen		33	68.225	0.48369		767
Synonymous	0.618	64	70.6	0.906	0.00000353	716
Loss of Function	2.11	11	21.6	0.510	0.00000108	277

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000178	0.000178
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000546	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.000118	0.000114
Middle Eastern	0.0000546	0.0000544
South Asian	0.000369	0.000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the radical-mediated insertion of two sulfur atoms into the C-6 and C-8 positions of the octanoyl moiety bound to the lipoyl domains of lipoate-dependent enzymes, thereby converting the octanoylated domains into lipoylated derivatives. {ECO:0000255|HAMAP-Rule:MF_03123}.
• Disease: DISEASE: Hyperglycinemia, lactic acidosis, and seizures (HGCLAS) [MIM:614462]: An enzymatic defect resulting in an autosomal recessive disorder of mitochondrial metabolism. It is characterized by early-onset lactic acidosis, severe encephalomyopathy, and a pyruvate oxidation defect. Affected individuals have neonatal-onset epilepsy, poor growth, psychomotor retardation, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine. {ECO:0000269|PubMed:22152680}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Lipoic acid metabolism - Homo sapiens (human);Metabolism of amino acids and derivatives;Metabolism;Glyoxylate metabolism and glycine degradation;lipoate biosynthesis and incorporation (Consensus)

Recessive Scores

• pRec: 0.358

Intolerance Scores

• loftool: 0.576
• rvis_EVS: -0.38
• rvis_percentile_EVS: 27.69

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.983

Gene Damage Prediction

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

Gene ontology

• Biological process: neural tube closure;inflammatory response;response to oxidative stress;lipoate biosynthetic process;protein lipoylation;response to lipopolysaccharide;cellular nitrogen compound metabolic process
• Cellular component: mitochondrion;mitochondrial matrix
• Molecular function: lipoate synthase activity;metal ion binding;4 iron, 4 sulfur cluster binding