9-137790891-C-T

Variant names:

• chr9-137790891-C-T
• rs587780332
• NM_024757.5:c.2426C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_024757.5(EHMT1):​c.2426C>T​(p.Pro809Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P809R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 7.79
• Publications: 10 publications found

Genes affected

EHMT1 (HGNC:24650): (euchromatic histone lysine methyltransferase 1) The protein encoded by this gene is a histone methyltransferase that methylates the lysine-9 position of histone H3. This action marks the genomic region packaged with these methylated histones for transcriptional repression. This protein may be involved in the silencing of MYC- and E2F-responsive genes and therefore could play a role in the G0/G1 cell cycle transition. Defects in this gene are a cause of chromosome 9q subtelomeric deletion syndrome (9q-syndrome, also known as Kleefstra syndrome). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]

EHMT1 Gene-Disease associations (from GenCC):

• Kleefstra syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Kleefstra syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-137790891-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1791094.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 9-137790891-C-T is Pathogenic according to our data. Variant chr9-137790891-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 128978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024757.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	NM_024757.5	MANE Select	c.2426C>T	p.Pro809Leu	missense	Exon 16 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.2405C>T	p.Pro802Leu	missense	Exon 16 of 27	NP_001341192.1
	EHMT1	NM_001354259.2		c.2333C>T	p.Pro778Leu	missense	Exon 15 of 16	NP_001341188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.2426C>T	p.Pro809Leu	missense	Exon 16 of 27	ENSP00000417980.1
	EHMT1	ENST00000482340.5	TSL:5	c.-5C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	ENSP00000486748.1
	EHMT1	ENST00000493484.5	TSL:3	c.-5C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	ENSP00000486503.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kleefstra syndrome 1 Pathogenic:5

Sep 05, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EHMT1 c.2426C>T variant is classified as PATHOGENIC (PS2, PS3, PS4, PP3) The EHMT1 c.2426C>T variant is a single nucleotide change in exon 16/27 of the EHMT1 gene, which is predicted to change the amino acid proline at position 809 in the protein to leucine. This variant has been identified as a de novo variant in this patient, although was detected in a very small proportion of reads in the mother (2 of 72, ~3%) (PS2). It has also been reported as de novo in an individual with Kleefstra syndrome in the literature, along with another unrelated Kleefstra syndrome case (PMID: 28057753; PS4). This variant is absent from population databases (PM2). Functional studies have demonstrated the variant leads to protein misfolding and aberrant target recognition via disrupted histone mark binding (PS3). Computational predictions support a deleterious effect on the gene or gene product (PP3). This variant has been reported in dbSNP (rs587780332) and has been reported as likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 128978), and damaging for Kleefstra syndrome in HGMD (CM172582).

Sep 01, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is absent from gnomAD (v2, v3 and v4); This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been classified as likely pathogenic and pathogenic by clinical laboratories (ClinVar, DECIPHER), and reported in the literature in individuals with Kleefstra syndrome (PMIDs: 39696517, 28057753); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from Pro to Leu; This variant is heterozygous; This gene is associated with autosomal dominant disease; Loss of function is a known mechanism of disease in this gene and is associated with Kleefstra syndrome 1 (MIM#610253); Inheritance information for this variant is not currently available in this individual.

Feb 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects EHMT1 function (PMID: 28057753). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 128978). This missense change has been observed in individual(s) with clinical features of Kleefstra syndrome (PMID: 28057753, 29276005, 31785789, 33767182). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 809 of the EHMT1 protein (p.Pro809Leu).

Jan 13, 2024

Genetics Laboratory, The Affiliated Women's and Children's Hospital of Qingdao University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

c.2426C>T (exon16, NM_024757), resulting in the amino acid change p.P809L, a missense mutation. The mutation was initially determined to be a pathogenic mutation (Pathogenic) PS2+PS4+PM2+PP3 according to the ACMG guidelines:  PS2: After family validation analysis, there is no mutation at this locus in the subject's father and no mutation at this locus in the subject's mother, and this variant is a spontaneous mutation;  PS4: cases of this locus (Kleefstra syndrome) have been reported in the literature database, with the variant labeled DM (pathogenic mutation), ClinVar The pathogenicity analysis of this locus in the ClinVar database is Conflicting interpretations of pathogenicity,- ;  PM2: the frequency in the normal population database is -, a low-frequency variant;  PP3: Bioinformatics protein function comprehensive prediction software REVEL predicted the results as harmful, SIFT, PolyPhen_2, MutationTaster , GERP+ predicted the results as harmful, harmful, harmful, harmful, harmful, respectively;

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

not provided Pathogenic:2 Uncertain:1

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 18, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Nov 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.9	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.79		Loss of disorder (P = 0.0443)
MVP		0.75
MPC		1.8
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.93
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587780332; hg19: chr9-140685343; COSMIC: COSV58377558; COSMIC: COSV58377558;