KARS1

protein-coding

lysyl-tRNA synthetase 1, the group of Aminoacyl tRNA synthetases, Class II

Gene summary

Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. Lysyl-tRNA synthetase is a homodimer localized to the cytoplasm which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

DFNB89
KARS

MANE transcript

NM_005548.3

Inheritance

ClinVar variants

P:49U:242B:96

Top phenotype

Deafness, autosomal recessive 89; Deafness, congenital, and adult-onset progressive leukoencephalopathy; Leukoencephalopathy, progressive, infantile-onset, with or without deafness

gnomAD constraint

pLI —, LoF o/e 0.61

Max pathogenic AF

—

Genomic locus

chr16:75,627,474-75,648,643

External References & Databases

Ensembl (ENSG00000065427)

Transcript & Mutation Effects

hg38 • Region Span ~21.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease recessive intermediate BMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013338

Submitter: PanelApp Australia

leukoencephalopathy, progressive, infantile-onset, with or without deafnessSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030893

Submitter: G2P

leukoencephalopathy, progressive, infantile-onset, with or without deafnessSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030893

Submitter: PanelApp Australia

Charcot-Marie-Tooth disease recessive intermediate BLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013338

Submitter: Labcorp Genetics (formerly Invitae)

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Charcot-Marie-Tooth disease recessive intermediate BSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013338

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 89STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013489

Submitter: PanelApp Australia

leukoencephalopathy, progressive, infantile-onset, with or without deafnessSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030893

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive nonsyndromic hearing loss 89STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013489

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive nonsyndromic hearing loss 89LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013489

Submitter: G2P

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The KARS gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 10/23/2017. This association was made using case-level data only. At least 4 missense variants have been reported in humans. KARS was first associated with this disease in humans as early as 2013 (Santos-Cortez et al.). Association is seen in at least 4 probands in 2 publications (23768514, 28887846). Variants in this gene segregated with disease in 10 additional family members. This gene-disease association is supported by expression and protein interaction studies. In summary, there is limited evidence to support this gene-disease association. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. Variants in KARS have been associated with a wide range of other phenotypes, including peripheral neuropathy, hypertrophic cardiomyopathy, mitochondrial disease, and developmental delays. While linkage analysis provides strong evidence for the DFNB89 locus, there is not strong evidence that KARS is the causative gene in this interval. This classification was approved by the ClinGen Hearing Loss Working Group on 2/27/2018.

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 89; Deafness, congenital, and adult-onset progressive leukoencephalopathy; Leukoencephalopathy, progressive, infantile-onset, with or without deafnessAR

Manifestation: Audiologic/Otolaryngologic; Gastrointestinal; Hematologic; Neurologic

Intervention: Audiologic/Otolaryngologic

Rationale: 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

Refs: 20920668; 23768514; 25330800; 28887846; 29615062; 30252186; 30715177; 30737337; 31116475; 33260297

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KARS1 variants in ClinVar

30 Conditions Cataloged

not providedTotal: 401

not specifiedTotal: 163

KARS1-related disorderTotal: 53

Leukoencephalopathy, progressive, infantile-onset, with or without deafnessTotal: 28

Autosomal recessive nonsyndromic hearing loss 89Total: 21

Charcot-Marie-Tooth disease recessive intermediate BTotal: 18

Deafness, congenital, and adult-onset progressive leukoencephalopathyTotal: 10

LEUKOENCEPHALOPATHY, PROGRESSIVE, INFANTILE-ONSET, WITH DEAFNESSTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005548.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	84 clinvar		87
missense	5 clinvar	26 clinvar	231 clinvar	11 clinvar	1 clinvar	274
nonsense	4 clinvar	6 clinvar	1 clinvar			11
start loss		1 clinvar	2 clinvar			3
frameshift	2 clinvar	2 clinvar	1 clinvar			5
splice donor/acceptor (+/-2bp)	2 clinvar	1 clinvar	4 clinvar			7
Total	13	36	242	95	1	387

Highest pathogenic variant AF is 0.00015923468

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005548.3	RefSeq	NP_005539.1	14	MANE Select
ENST00000302445.8	Ensembl	ENSP00000303043.3	14	MANE Select
NM_001130089.2	RefSeq	NP_001123561.1	14	Standard
NM_001378148.1	RefSeq	NP_001365077.1	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
kars	Danio rerio	Structure: trunk Quality: degenerate abnormal

Gene / Model

Organism

Observed Phenotype

kars

Danio rerio

Structure: trunk

Quality: degenerate

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
tRNA Aminoacylation
Translation
Metabolism of proteins
Metabolism of amino acids and derivatives

Biological Process

activation of MAPK activity
basophil activation involved in immune response
positive regulation of cytokine secretion involved in immune response
tRNA aminoacylation for protein translation
lysyl-tRNA aminoacylation

Molecular Function

tRNA binding
ATP adenylyltransferase activity
lysine-tRNA ligase activity
protein binding
ATP binding

Cellular Component

extracellular space
nucleus
mitochondrion
mitochondrial matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000319410
Coding exons: 14
Length: 20920
Individuals with no LoFs: 125719
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 125748
p: 0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.727	380	342	1.11	0.0000199	4145
Missense (PolyPhen)		113	126.2	0.89541		1600
Synonymous	-2.13	153	123	1.24	0.00000691	1175
Loss of Function	1.96	18	29.5	0.610	0.00000161	373

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000098	0.000098	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA (PubMed:9278442, PubMed:18029264, PubMed:18272479). When secreted, acts as a signaling molecule that induces immune response through the activation of monocyte/macrophages (PubMed:15851690). Catalyzes the synthesis of the signaling molecule diadenosine tetraphosphate (Ap4A), and thereby mediates disruption of the complex between HINT1 and MITF and the concomitant activation of MITF transcriptional activity (PubMed:5338216, PubMed:14975237, PubMed:19524539, PubMed:23159739). {ECO:0000269|PubMed:14975237, ECO:0000269|PubMed:15851690, ECO:0000269|PubMed:18029264, ECO:0000269|PubMed:19524539, ECO:0000269|PubMed:28887846, ECO:0000269|PubMed:5338216, ECO:0000269|PubMed:9278442}.;
Disease: DISEASE: Charcot-Marie-Tooth disease, recessive, intermediate type, B (CMTRIB) [MIM:613641]: A form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Recessive intermediate forms of Charcot-Marie-Tooth disease are characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec. {ECO:0000269|PubMed:20920668}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal recessive, 89 (DFNB89) [MIM:613916]: A form of non-syndromic deafness characterized by bilateral, prelingual, moderate to severe hearing loss affecting all frequencies. {ECO:0000269|PubMed:23768514, ECO:0000269|PubMed:28887846}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.351

Intolerance Scores

LoFtool: 0.342
RVIS EVS: -0.93
RVIS percentile EVS: 9.68

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.914

Gene Damage Prediction

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