SETD2

protein-coding

SET domain containing 2, histone lysine methyltransferase, the group of SET domain containing|Lysine methyltransferases

Gene summary

Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein belonging to a class of huntingtin interacting proteins characterized by WW motifs. This protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin. This protein also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II. [provided by RefSeq, Aug 2008]

MANE transcript

NM_014159.7

Inheritance

ClinVar variants

P:81U:882B:525

Top phenotype

Luscan-Lumish syndrome

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr3:47,016,428-47,164,113

External References & Databases

Ensembl (ENSG00000181555)

Transcript & Mutation Effects

hg38 • Region Span ~147.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Rabin-Pappas syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859331

Submitter: G2P

Rabin-Pappas syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859331

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal dominant 70LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0859333

Submitter: Ambry Genetics

Luscan-Lumish syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014791

Submitter: Ambry Genetics

Rabin-Pappas syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859331

Submitter: Labcorp Genetics (formerly Invitae)

SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0035706

Submitter: PanelApp Australia

SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowthSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0800477

Submitter: PanelApp Australia

SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowthDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0800477

Submitter: ClinGen

The *SETD2* gene encodes a histone lysine methyltransferase that plays an important role in chromatin-mediated regulation of gene expression. SETD2 can also interact with non-histone substrates and methylate microtubules and actin, thereby regulating cytoskeletal functions. Although protein truncating variants in *SETD2* had been observed in a cohort study of individuals with autism spectrum disorder in 2012 (O’Roak et al., PMID: 23160955), the first reports focusing on variants in *SETD2* as a cause of autosomal dominant *SETD2*-related neurodevelopmental disorder without or with macrocephaly/overgrowth were published in 2014 (Luscan et al., PMID: 24852293) and 2015 (Lumish et al., PMID: 26084711). The term selected for curation includes individuals with Luscan-Lumish syndrome (OMIM# 616831) and Intellectual developmental disorder, autosomal dominant 70 (OMIM# 620157). Affected individuals exhibit developmental delay or intellectual disability, motor delay, speech delay, hypotonia, autism spectrum disorder, and sometimes features such as macrocephaly, overgrowth, and dysmorphic features. Thirteen variants (7 frameshift, 4 nonsense, 1 recurrent missense, and 1 splice) that have been reported in 15 probands in 12 publications (PMIDs: 23160955, 24852293, 26084711, 27317772, 29681085, 31643139, 32710489, 33248444, 33766796, 36777730, 37025455, 37372360) are included in this curation. Most of the reported variants are *de novo*. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be loss of function. However, the mechanism of the recurrent missense variant (NM_014159.7:c.5219G>A, p.Arg1740Gln) reported in three individuals (PMID: 32710489) remains to be determined. Several other *de novo* missense variants were not scored given the absence of evidence of pathogenicity (PMIDs: 23160955, 24852293, 31643139, 33248444, 37372360). This gene-disease relationship is further supported by experimental evidence, including biochemical function and protein interaction studies. Other genes encoding histone lysine methyltransferases have also been implicated in neurodevelopmental disorders, including *SETD1A*, *SETD1B*, and *SETD5*. Furthermore, other genes belonging to the histone methyltransferase family have also been involved in overgrowth disorders (*DNMT3A* and *BRWD3*). In addition, POLR2A and TUBA1A, two proteins that interact with SETD2 (PMIDs: 16118227, 27518565), are also implicated in neurodevelopmental disorders. Of note, this gene has also been reported in relation to autosomal dominant *SETD2*-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome (MONDO:0035706), which was assessed separately. In summary, there is definitive evidence supporting the relationship between *SETD2* and autosomal dominant *SETD2*-related neurodevelopmental disorder without or with macrocephaly/overgrowth. 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 Intellectual Disability and Autism Gene Curation Expert Panel on October 4, 2023 (SOP Version 9).

SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0035706

Submitter: ClinGen

The *SETD2* gene encodes a histone lysine methyltransferase that plays an important role in chromatin-mediated regulation of gene expression. SETD2 can also interact with non-histone substrates and methylate microtubules and actin, thereby regulating cytoskeletal functions. *SETD2* was first reported in relation to autosomal dominant *SETD2*-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome in 2020 (Rabin et al., PMID: 32710489). Affected individuals exhibit severe global developmental delay and intellectual disability, microcephaly, hypotonia, respiratory insufficiency, failure to thrive, similar dysmorphic facial features and congenital anomalies affecting several organ systems. Other findings may include seizures, hearing loss, ophthalmologic defects, and structural brain abnormalities. Only one missense variant that has been reported in 12 probands with a *de novo* inheritance, NM_014159.7:c.5218C>T (p.Arg1740Trp), is included in this curation (PMID: 32710489). No functional studies have been performed and the mechanism of pathogenicity is unknown. Two additional *de novo* missense variants have been reported in two probands (PMID: 37372360) but they are not included in this curation because their pathogenicity remains unclear. Of note, *SETD2* has also been reported in relation to autosomal dominant *SETD2*-related neurodevelopmental disorder without or with macrocephaly/overgrowth, which was assessed separately. This gene-disease relationship is further supported by experimental evidence, including biochemical function and protein interaction studies. Other genes encoding histone lysine methyltransferases have also been implicated in neurodevelopmental disorders, including *SETD1A*, *SETD1B*, and *SETD5*. In addition, POLR2A and TUBA1A, two proteins that interact with SETD2 (PMIDs: 16118227, 27518565), are also implicated in neurodevelopmental disorders. In summary, there is strong evidence supporting the relationship between *SETD2* and autosomal dominant *SETD2*-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome. However, at present, all genetic evidence is derived from only one recurrent variant reported in a single publication. We will re-evaluate this gene-disease relationship in the future if more variants are reported. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 4, 2023 (SOP Version 9).

Luscan-Lumish syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014791

Submitter: G2P

Luscan-Lumish syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014791

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Luscan-Lumish syndromeAD

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: 22495309; 23160955; 24852293; 25363768; 26084711

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SETD2 variants in ClinVar

28 Conditions Cataloged

Luscan-Lumish syndromeTotal: 856

not providedTotal: 532

Inborn genetic diseasesTotal: 273

not specifiedTotal: 209

SETD2-related disorderTotal: 120

Intellectual developmental disorder, autosomal dominant 70Total: 25

Rabin-Pappas syndromeTotal: 18

Autism spectrum disorderTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014159.7. 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			7 clinvar	270 clinvar	12 clinvar	289
missense	3 clinvar	9 clinvar	826 clinvar	200 clinvar	41 clinvar	1079
nonsense	19 clinvar	10 clinvar	13 clinvar	1 clinvar		43
start loss			3 clinvar	1 clinvar		4
frameshift	21 clinvar	12 clinvar	15 clinvar			48
splice donor/acceptor (+/-2bp)	3 clinvar	4 clinvar	18 clinvar			25
Total	46	35	882	472	53	1488

Highest pathogenic variant AF is 0.000006572893

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014159.7	RefSeq	NP_054878.5	21	MANE Select
ENST00000409792.4	Ensembl	ENSP00000386759.3	21	MANE Select
NM_001349370.3	RefSeq	NP_001336299.1	19	Standard
ENST00000330022.11	Ensembl	ENSP00000332415.7	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysine degradation - Homo sapiens (human)
Histone Modifications
Mesodermal Commitment Pathway
Pathways Affected in Adenoid Cystic Carcinoma
Pathways in clear cell renal cell carcinoma

Biological Process

angiogenesis
morphogenesis of a branching structure
neural tube closure
mismatch repair
regulation of transcription, DNA-templated

Molecular Function

protein binding
protein-lysine N-methyltransferase activity
histone-lysine N-methyltransferase activity
alpha-tubulin binding
metal ion binding

Cellular Component

nucleus
nucleoplasm
chromosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000409792
Coding exons: 21
Length: 147539
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125748
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.05	1011	1.32e+3	0.764	0.0000687	16825
Missense (PolyPhen)		263	496.46	0.52975		6221
Synonymous	0.452	459	471	0.974	0.0000239	4934
Loss of Function	8.30	14	106	0.132	0.00000611	1389

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00050	0.00050	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000097	0.000097	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Histone methyltransferase that specifically trimethylates 'Lys-36' of histone H3 (H3K36me3) using dimethylated 'Lys-36' (H3K36me2) as substrate (PubMed:16118227, PubMed:19141475, PubMed:21526191, PubMed:21792193, PubMed:23043551, PubMed:27474439). Represents the main enzyme generating H3K36me3, a specific tag for epigenetic transcriptional activation (By similarity). Plays a role in chromatin structure modulation during elongation by coordinating recruitment of the FACT complex and by interacting with hyperphosphorylated POLR2A (PubMed:23325844). Acts as a key regulator of DNA mismatch repair in G1 and early S phase by generating H3K36me3, a mark required to recruit MSH6 subunit of the MutS alpha complex: early recruitment of the MutS alpha complex to chromatin to be replicated allows a quick identification of mismatch DNA to initiate the mismatch repair reaction (PubMed:23622243). Required for DNA double-strand break repair in response to DNA damage: acts by mediating formation of H3K36me3, promoting recruitment of RAD51 and DNA repair via homologous recombination (HR) (PubMed:24843002). Acts as a tumor suppressor (PubMed:24509477). H3K36me3 also plays an essential role in the maintenance of a heterochromatic state, by recruiting DNA methyltransferase DNMT3A (PubMed:27317772). H3K36me3 is also enhanced in intron-containing genes, suggesting that SETD2 recruitment is enhanced by splicing and that splicing is coupled to recruitment of elongating RNA polymerase (PubMed:21792193). Required during angiogenesis (By similarity). Required for endoderm development by promoting embryonic stem cell differentiation toward endoderm: acts by mediating formation of H3K36me3 in distal promoter regions of FGFR3, leading to regulate transcription initiation of FGFR3 (By similarity). In addition to histones, also mediates methylation of other proteins, such as tubulins and STAT1 (PubMed:27518565, PubMed:28753426). Trimethylates 'Lys-40' of alpha-tubulins such as TUBA1B (alpha- TubK40me3); alpha-TubK40me3 is required for normal mitosis and cytokinesis and may be a specific tag in cytoskeletal remodeling (PubMed:27518565). Involved in interferon-alpha-induced antiviral defense by mediating both monomethylation of STAT1 at 'Lys-525' and catalyzing H3K36me3 on promoters of some interferon-stimulated genes (ISGs) to activate gene transcription (PubMed:28753426). {ECO:0000250|UniProtKB:E9Q5F9, ECO:0000269|PubMed:16118227, ECO:0000269|PubMed:19141475, ECO:0000269|PubMed:21526191, ECO:0000269|PubMed:21792193, ECO:0000269|PubMed:23043551, ECO:0000269|PubMed:23325844, ECO:0000269|PubMed:23622243, ECO:0000269|PubMed:24509477, ECO:0000269|PubMed:24843002, ECO:0000269|PubMed:27317772, ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:27518565, ECO:0000269|PubMed:28753426}.;
Disease: DISEASE: Renal cell carcinoma (RCC) [MIM:144700]: Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma. Clear cell renal cell carcinoma is the most common subtype. {ECO:0000269|PubMed:20054297, ECO:0000269|PubMed:23622243, ECO:0000269|PubMed:23792563, ECO:0000269|PubMed:25728682}. Note=The disease may be caused by mutations affecting the gene represented in this entry. Defects of SETD2 are associated with loss of DNA methylation at non-promoter regions (PubMed:23792563). SETD2 defects lead to aberrant and reduced nucleosome compaction and chromatin association of key replication proteins, such as MCM7 and DNA polymerase delta, leading to hinder replication fork progression and prevent loading of RAD51 homologous recombination repair factor at DNA breaks (PubMed:25728682). {ECO:0000269|PubMed:23792563, ECO:0000269|PubMed:25728682}.; DISEASE: Luscan-Lumish syndrome (LLS) [MIM:616831]: An autosomal dominant syndrome with a variable phenotype. Clinical features include macrocephaly, distinctive facial appearance, postnatal overgrowth, various degrees of learning difficulties, autism spectrum disorder, and intellectual disability. {ECO:0000269|PubMed:23160955, ECO:0000269|PubMed:24852293, ECO:0000269|PubMed:26084711, ECO:0000269|PubMed:27317772}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Leukemia, acute lymphoblastic (ALL) [MIM:613065]: A subtype of acute leukemia, a cancer of the white blood cells. ALL is a malignant disease of bone marrow and the most common malignancy diagnosed in children. The malignant cells are lymphoid precursor cells (lymphoblasts) that are arrested in an early stage of development. The lymphoblasts replace the normal marrow elements, resulting in a marked decrease in the production of normal blood cells. Consequently, anemia, thrombocytopenia, and neutropenia occur to varying degrees. The lymphoblasts also proliferate in organs other than the marrow, particularly the liver, spleen, and lymphnodes. {ECO:0000269|PubMed:24509477, ECO:0000269|PubMed:24662245}. Note=The disease may be caused by mutations affecting distinct genetic loci, including the gene represented in this entry.; DISEASE: Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. {ECO:0000269|PubMed:16314571, ECO:0000269|PubMed:24509477}. Note=The disease may be caused by mutations affecting distinct genetic loci, including the gene represented in this entry.;

Recessive Scores

pRec: 0.390

Intolerance Scores

LoFtool: 0.0294
RVIS EVS: -0.94
RVIS percentile EVS: 9.42

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.511

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High