KITLG

protein-coding

KIT ligand

Gene summary

This gene encodes the ligand of the tyrosine-kinase receptor encoded by the KIT locus. This ligand is a pleiotropic factor that acts in utero in germ cell and neural cell development, and hematopoiesis, all believed to reflect a role in cell migration. In adults, it functions pleiotropically, while mostly noted for its continued requirement in hematopoiesis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

MANE transcript

NM_000899.5

Inheritance

AD, AR

ClinVar variants

P:12U:86B:25

Top phenotype

Deafness, autosomal dominant 69; Waardenburg syndrome, type 2F

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr12:88,492,793-88,580,851

External References & Databases

Ensembl (ENSG00000049130)

Transcript & Mutation Effects

hg38 • Region Span ~88.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hyperpigmentation with or without hypopigmentation, familial progressiveMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007771

Submitter: Ambry Genetics

Waardenburg syndrome type 2LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019517

Submitter: G2P

Waardenburg syndrome 2FLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030983

Submitter: Ambry Genetics

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

The KITLG gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 1/5/2018. This association was made using case-level data only. At least 2 variants, an in-frame indel and nonsense, have been reported in humans. KITLG was first associated with this disease in humans as early as 2015 (Zazo Seco et al.). Association is seen in at least 2 probands in 1 publications (26522471). Variants in this gene segregated with disease in 9 additional family members. There is evidence for reduced penetrance of a KITLG variant in one family. This gene-disease association is supported by an expression study and a protein interaction assay. 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. This classification was approved by the ClinGen Hearing Loss Working Group on 1/16/2018.

autosomal dominant nonsyndromic hearing loss 69STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014738

Submitter: Labcorp Genetics (formerly Invitae)

Waardenburg syndrome type 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019517

Submitter: Orphanet

familial progressive hyper- and hypopigmentationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017239

Submitter: Orphanet

familial progressive hyperpigmentationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013648

Submitter: Orphanet

Waardenburg syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018094

Submitter: PanelApp Australia

Waardenburg syndrome 2FLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0030983

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 69; Waardenburg syndrome, type 2FAD/AR

Manifestation: Audiologic/Otolaryngologic; Dermatologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 18083106; 17952075; 19375057; 26522471; 28504826; 35543077

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KITLG variants in ClinVar

7 Conditions Cataloged

not providedTotal: 111

not specifiedTotal: 25

Inborn genetic diseasesTotal: 19

KITLG-related disorderTotal: 14

Hyperpigmentation with or without hypopigmentation, familial progressiveTotal: 6

Waardenburg syndrome 2FTotal: 5

Autosomal dominant nonsyndromic hearing loss 69Total: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000899.5. 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			4 clinvar	18 clinvar	1 clinvar	23
missense	6 clinvar	3 clinvar	64 clinvar	5 clinvar	1 clinvar	79
nonsense			3 clinvar			3
start loss			2 clinvar			2
frameshift	1 clinvar		8 clinvar			9
splice donor/acceptor (+/-2bp)		2 clinvar	5 clinvar			7
Total	7	5	86	23	2	123

Highest pathogenic variant AF is 0.00006889545

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000899.5	RefSeq	NP_000890.1	9	MANE Select
ENST00000644744.1	Ensembl	ENSP00000495951.1	9	MANE Select
NM_003994.6	RefSeq	NP_003985.2	8	Standard
ENST00000347404.10	Ensembl	ENSP00000054216.5	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
kitlga	Danio rerio	Structure: melanocyte Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

kitlga

Danio rerio

Structure: melanocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Rap1 signaling pathway - Homo sapiens (human)
Ras signaling pathway - Homo sapiens (human)
MAPK signaling pathway - Homo sapiens (human)
Phospholipase D signaling pathway - Homo sapiens (human)

Biological Process

MAPK cascade
ovarian follicle development
neural crest cell migration
positive regulation of leukocyte migration
positive regulation of myeloid leukocyte differentiation

Molecular Function

Ras guanyl-nucleotide exchange factor activity
cytokine activity
stem cell factor receptor binding
protein binding
growth factor activity

Cellular Component

extracellular region
extracellular space
cytoplasm
cytoskeleton
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000228280
Coding exons: 9
Length: 88059
Individuals with no LoFs: 125661
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125665
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.811	114	141	0.808	0.00000658	1826
Missense (PolyPhen)		43	62.916	0.68345		871
Synonymous	0.106	47	47.9	0.980	0.00000231	482
Loss of Function	3.11	2	15.0	0.133	6.31e-7	197

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Ligand for the receptor-type protein-tyrosine kinase KIT. Plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. KITLG/SCF binding can activate several signaling pathways. Promotes phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, and subsequent activation of the kinase AKT1. KITLG/SCF and KIT also transmit signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. KITLG/SCF and KIT promote activation of STAT family members STAT1, STAT3 and STAT5. KITLG/SCF and KIT promote activation of PLCG1, leading to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5- trisphosphate. KITLG/SCF acts synergistically with other cytokines, probably interleukins.;
Disease: DISEASE: Hyperpigmentation with or without hypopigmentation, familial progressive (FPHH) [MIM:145250]: A disorder characterized by hyperpigmented patches in the skin, present in early infancy and increasing in size and number with age. Hyperpigmentation has variable intensity, and sometimes is associated with cafe-au-lait macules and larger hypopigmented ash-leaf macules. {ECO:0000269|PubMed:19375057}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, congenital, unilateral or asymmetric (DCUA) [MIM:616697]: An autosomal dominant form of non-syndromic, sensorineural deafness characterized by inability to hear affecting one ear. Some patients suffers from asymmetric, bilateral hearing loss. {ECO:0000269|PubMed:26522471}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.801

Intolerance Scores

LoFtool: 0.564
RVIS EVS: -0.18
RVIS percentile EVS: 39.95

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.767

Gene Damage Prediction

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