KMT5B

protein-coding

lysine methyltransferase 5B, the group of Lysine methyltransferases

Gene summary

This gene encodes a protein that contains a SET domain. SET domains appear to be protein-protein interaction domains that mediate interactions with a family of proteins that display similarity with dual-specificity phosphatases (dsPTPases). The function of this gene has not been determined. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

Previous symbols:

SUV420H1

MANE transcript

NM_017635.5

Inheritance

ClinVar variants

P:87U:133B:63

Top phenotype

Intellectual developmental disorder, autosomal dominant 51

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr11:68,154,863-68,213,852

External References & Databases

Ensembl (ENSG00000110066)

Transcript & Mutation Effects

hg38 • Region Span ~59.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

The KMT5B gene, which was previously known as SUV420H1, is located on chromosome 11 at 11q13.2 and encodes lysine methyltransferase 5B. Through its role as a histone methyltransferase, KMT5B 'writes' H4K20 methylation marks and regulates transcription. KMT5B was first reported in relation to autosomal dominant neurodevelopmental disorders in 2017 (Stessman et al., PMID:28191889), although de novo variants had been reported earlier (Iossifov et al., 2014, PMID: 25363768; Lelieveld et al., 2016, PMID: 27479843). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Nine unique variants (6 frameshift, 1 nonsense, 1 canonical splice, and 1 missense) have been reported in nine probands from three publications ( Stessman et al., 2017, PMID:28191889; Faundes et al., 2018, PMID: 29276005; Trinh et al., 2019, PMID 31238879). Eight of the variants occurred de novo, while the other was. The mechanism of disease has not yet been clearly established, but haploinsufficiency has been suggested. This gene-disease relationship is also supported by shared function with other genes associated with neurodevelopmental disorders (PMID: 28191889). A Drosophila knockdown model shows impaired habituation in a behavioral assay (PMID: 28191889) and heterozygous KMT5B knockout mice show smaller body and brain size and deficits in neonatal reflexes, sociability, stress-induced grooming, and behaviors related to anxiety, depression, and fear learning (Wickramasekara et al., 2021, PMID 33871180). In summary, KMT5B is definitively associated with autosomal dominant KMT5B-related neurodevelopmental disorders. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 11.03.2021 (SOP Version 8).

intellectual developmental disorder, autosomal dominant 51DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0030917

Submitter: G2P

intellectual developmental disorder, autosomal dominant 51STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030917

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal dominant 51STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030917

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal dominant 51STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030917

Submitter: Illumina

The KMT5B gene, which was previously known as SUV420H1, is located on chromosome 11 at 11q13.2 and encodes lysine methyltransferase 5B. Through its role as a histone methyltransferase, KMT5B 'writes' H4K20 methylation marks and regulates transcription. KMT5B was first reported in relation to an autosomal dominant neurodevelopmental disorder in 2017 (28191889: Stessman et al. 2017), although de novo variants had been reported earlier (25363768: Iossifov et al. 2014; 27479843: Lelieveld et al. 2016). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included seven unique variants (four frameshift, one stop-gained, one canonical splice, and one missense) identified in seven cases from three publications (19344873: Firth et al. 2009; 27479843: Lelieveld et al. 2016; 28191889: Stessman et al. 2017). No segregation evidence was available, and five of the variants occurred de novo. The mechanism of disease has not yet been clearly established, but haploinsufficiency has been suggested. This gene-disease relationship is also supported by a shared function with other genes associated with neurodevelopmental disorders, expression in the brain in a temporally and spatially regulated manner that correlates with neurogenesis, and a Drosophila knockdown model that shows impaired habituation in a behavioral assay (28191889: Stessman et al. 2017). In summary, there is strong evidence to support the relationship between KMT5B and autosomal dominant KMT5B-related neurodevelopmental disorder. Additional reports in humans published more than three years since the first proposal are needed to reach a definitive classification.

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 51AD

Manifestation: Craniofacial; 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: 25363768; 28191889; 29276005

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KMT5B variants in ClinVar

19 Conditions Cataloged

not providedTotal: 161

Intellectual disability, autosomal dominant 51Total: 86

KMT5B-related disorderTotal: 41

Inborn genetic diseasesTotal: 36

not specifiedTotal: 23

See casesTotal: 6

Intellectual disabilityTotal: 2

Autism spectrum disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017635.5. 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				30 clinvar	2 clinvar	32
missense	2 clinvar	14 clinvar	124 clinvar	30 clinvar		170
nonsense	11 clinvar	11 clinvar	1 clinvar			23
start loss						0
frameshift	21 clinvar	19 clinvar	5 clinvar			45
splice donor/acceptor (+/-2bp)		9 clinvar	3 clinvar	1 clinvar		13
Total	34	53	133	61	2	283

Highest pathogenic variant AF is 0.0000014130981

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 68 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017635.5	RefSeq	NP_060105.3	10	MANE Select
ENST00000304363.9	Ensembl	ENSP00000305899.4	10	MANE Select
NM_001300907.1	RefSeq	NP_001287836.1	7	Standard
NM_001300908.2	RefSeq	NP_001287837.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysine degradation - Homo sapiens (human)
Histone Modifications
PKMTs methylate histone lysines
Chromatin modifying enzymes
Glucocorticoid receptor regulatory network

Biological Process

muscle organ development
histone H4-K20 trimethylation

Molecular Function

histone-lysine N-methyltransferase activity
histone methyltransferase activity (H4-K20 specific)

Cellular Component

condensed nuclear chromosome, centromeric region
nucleus
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000304363
Coding exons: 10
Length: 58966
Individuals with no LoFs: 125680
Homozygous LoFs: 0
Heterozygous LoFs: 38
Defined: 125718
p: 0.000151

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.79	306	478	0.641	0.0000261	5844
Missense (PolyPhen)		46	136.74	0.33639		1684
Synonymous	1.46	160	185	0.863	0.0000113	1652
Loss of Function	5.72	0	38.1	0.00	0.00000228	488

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	0.0020	0.0019	notable
Finnish	0	0.0	absent
European (Non-Finnish)	0.000020	0.000018	rare
South Asian	0	0.0	absent
Other	0.00018	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Histone methyltransferase that specifically trimethylates 'Lys-20' of histone H4. H4 'Lys-20' trimethylation represents a specific tag for epigenetic transcriptional repression. Mainly functions in pericentric heterochromatin regions, thereby playing a central role in the establishment of constitutive heterochromatin in these regions. KMT5B is targeted to histone H3 via its interaction with RB1 family proteins (RB1, RBL1 and RBL2) (By similarity). Plays a role in myogenesis by regulating the expression of target genes, such as EID3. {ECO:0000250, ECO:0000269|PubMed:23720823}.;
Disease: DISEASE: Mental retardation, autosomal dominant 51 (MRD51) [MIM:617788]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:28191889}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.107

Intolerance Scores

RVIS EVS: -0.95
RVIS percentile EVS: 9.21

Essentials

Essential (gene trap): N