KDM5C

protein-coding

lysine demethylase 5C, the group of Lysine demethylases|MicroRNA protein coding host genes|AT-rich interaction domain containing|PHD finger proteins

Gene summary

This gene is a member of the SMCY homolog family and encodes a protein with one ARID domain, one JmjC domain, one JmjN domain and two PHD-type zinc fingers. The DNA-binding motifs suggest this protein is involved in the regulation of transcription and chromatin remodeling. Mutations in this gene have been associated with X-linked cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

Previous symbols:

SMCX
JARID1C
MRX13

MANE transcript

NM_004187.5

Inheritance

ClinVar variants

P:212U:557B:297

Top phenotype

Intellectual developmental disorder, X-linked, syndromic, Claes-Jensen type

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chrX:53,176,277-53,225,422

External References & Databases

Ensembl (ENSG00000126012)

Transcript & Mutation Effects

hg38 • Region Span ~49.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked, syndromic, Claes-Jensen typeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010355

Submitter: Ambry Genetics

X-linked complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

*KDM5C* is located on chromosome Xp11.22 and encodes a lysine demethylase involved in transcriptional regulation. *KDM5C* was first reported in relation to X-linked complex neurodevelopmental disorder in 2005 (Jensen et al., PMID: 15586325). The clinical features of affected males include global developmental delay, intellectual disability (varying from mild to severe), speech impairment, seizures, short stature, mild dysmorphic features, and behavioral disorders including aggressive behavior, hyperactivity, and autism or autistic features. Other findings observed in some individuals include microcephaly, progressive spasticity, and visual problems. Female carriers are usually unaffected but can sometimes be mildly affected and present with short stature, dysmorphic features, or mild cognitive impairment. Eleven variants (nonsense, frameshift, splice, and missense) that have been reported in 11 probands in four publications (PMIDs: 15586325, 18697827, 21575681, 22326837) are included in this curation. Variants in this gene segregated with disease in additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. Patients with pathogenic variants display a specific peripheral blood epi-signature (PMID: 29456765). This gene-disease relationship is also supported by biochemical function, a mouse model (PMID: 26804915), and experiments in knockdown neurons (PMID: 17320160) and in patient-derived induced pluripotent stem cells (PMID: 38383780). Several other genes encoding lysine demethylases are involved in intellectual disability and autism. In summary, there is definitive evidence supporting the relationship between *KDM5C* and X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 19, 2018. It was reevaluated on August 12, 2026 (SOP Version 12). Although additional cases and experimental evidence were added, the classification did not change.

intellectual developmental disorder, X-linked, syndromic, Claes-Jensen typeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010355

Submitter: G2P

intellectual developmental disorder, X-linked, syndromic, Claes-Jensen typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010355

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, X-linked, syndromic, Claes-Jensen typeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010355

Submitter: Orphanet

intellectual developmental disorder, X-linked, syndromic, Claes-Jensen typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010355

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked, syndromic, Claes-Jensen typeXL

Manifestation: Craniofacial; Genitourinary; Musculoskeletal; Neurologic

Intervention: General

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: 10982473; 15586325; 16538222; 18697827; 18203167; 19826449; 21575681; 22326837; 22611640

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KDM5C variants in ClinVar

17 Conditions Cataloged

Spastic paraplegiaTotal: 470

not providedTotal: 433

Syndromic X-linked intellectual disability Claes-Jensen typeTotal: 186

Inborn genetic diseasesTotal: 136

not specifiedTotal: 96

KDM5C-related disorderTotal: 58

Intellectual disabilityTotal: 14

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004187.5. 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			36 clinvar	204 clinvar	19 clinvar	259
missense	11 clinvar	42 clinvar	466 clinvar	59 clinvar	15 clinvar	593
nonsense	38 clinvar	17 clinvar	21 clinvar			76
start loss		1 clinvar				1
frameshift	48 clinvar	31 clinvar	1 clinvar			80
splice donor/acceptor (+/-2bp)	4 clinvar	20 clinvar	33 clinvar			57
Total	101	111	557	263	34	1066

Highest pathogenic variant AF is 0.000026458132

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004187.5	RefSeq	NP_004178.2	26	MANE Select
ENST00000375401.8	Ensembl	ENSP00000364550.4	26	MANE Select
NM_001146702.2	RefSeq	NP_001140174.1	24	Standard
NM_001282622.3	RefSeq	NP_001269551.1	26	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
kdm5c	Danio rerio	Structure: whole organism Quality: curved ventral abnormal

Gene / Model

Organism

Observed Phenotype

kdm5c

Danio rerio

Structure: whole organism

Quality: curved ventral

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pathways in clear cell renal cell carcinoma
HDMs demethylate histones
Chromatin modifying enzymes
Chromatin organization

Biological Process

negative regulation of transcription by RNA polymerase II
chromatin remodeling
histone H3-K4 demethylation
histone H3-K4 demethylation, trimethyl-H3-K4-specific
negative regulation of transcription, DNA-templated

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
protein binding
zinc ion binding
histone demethylase activity

Cellular Component

nucleus
nucleoplasm
cytosol
histone methyltransferase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000375401
Coding exons: 26
Length: 34102
Individuals with no LoFs: 125742
Homozygous LoFs: 1
Heterozygous LoFs: 4
Defined: 125747
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.15	293	667	0.439	0.0000572	10067
Missense (PolyPhen)		43	263.2	0.16337		4170
Synonymous	-0.582	272	260	1.05	0.0000201	3210
Loss of Function	6.38	4	55.1	0.0726	0.00000433	846

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000076	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)	0.000013	0.0000088	rare
South Asian	0.00016	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Histone demethylase that specifically demethylates 'Lys- 4' of histone H3, thereby playing a central role in histone code (PubMed:28262558). Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. Participates in transcriptional repression of neuronal genes by recruiting histone deacetylases and REST at neuron-restrictive silencer elements. Represses the CLOCK-ARNTL/BMAL1 heterodimer- mediated transcriptional activation of the core clock component PER2 (By similarity). {ECO:0000250|UniProtKB:P41230, ECO:0000269|PubMed:17320160, ECO:0000269|PubMed:17320161, ECO:0000269|PubMed:17468742, ECO:0000269|PubMed:26645689, ECO:0000269|PubMed:28262558}.;
Disease: DISEASE: Mental retardation, X-linked, syndromic, Claes-Jensen type (MRXSCJ) [MIM:300534]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRXSCJ patients manifest mental retardation associated with variable features such as slowly progressive spastic paraplegia, seizures, facial dysmorphism. {ECO:0000269|PubMed:15586325, ECO:0000269|PubMed:16538222, ECO:0000269|PubMed:16541399, ECO:0000269|PubMed:17320160, ECO:0000269|PubMed:17468742, ECO:0000269|PubMed:23356856, ECO:0000269|PubMed:25666439}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.193

Intolerance Scores

LoFtool: 0.0636
RVIS EVS: -1.51
RVIS percentile EVS: 3.5

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.730

Gene Damage Prediction

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