NM_024757.5(EHMT1):c.2704C>T (p.Arg902Ter) AND Kleefstra syndrome 1

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Apr 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001808728.6

Allele description [Variation Report for NM_024757.5(EHMT1):c.2704C>T (p.Arg902Ter)]

NM_024757.5(EHMT1):c.2704C>T (p.Arg902Ter)

Gene:

EHMT1:euchromatic histone lysine methyltransferase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.3

Genomic location:

Preferred name:

NM_024757.5(EHMT1):c.2704C>T (p.Arg902Ter)

Other names:

p.Arg902Ter

HGVS:

NC_000009.12:g.137800976C>T
NG_011776.1:g.186985C>T
NM_001354263.2:c.2683C>T
NM_024757.5:c.2704C>TMANE SELECT
NP_001341192.1:p.Arg895Ter
NP_079033.4:p.Arg902Ter
NC_000009.11:g.140695428C>T
NM_024757.4:c.2704C>T

Protein change:

R895*

Links:

dbSNP: rs886041844

NCBI 1000 Genomes Browser:

rs886041844

Molecular consequence:

NM_001354263.2:c.2683C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_024757.5:c.2704C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Kleefstra syndrome 1
Identifiers:: MONDO: MONDO:0027407; MedGen: C0795833; Orphanet: 261494; OMIM: 610253

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002058486	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002060419	Laboratory of Human Genetics, Universidade de São Paulo	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 16, 2019)	de novo	research	PubMed (1) [See all records that cite this PMID]
SCV004458735	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 17, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16826528, 19264732, 28492532
SCV005045819	Laboratory of Genetics, Children's Clinical University Hospital Latvia	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	de novo	curation	PubMed (2) [See all records that cite these PMIDs] 25741868, 39013458

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	curation
Brazilian	de novo	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome.

Kleefstra T, Brunner HG, Amiel J, Oudakker AR, Nillesen WM, Magee A, Geneviève D, Cormier-Daire V, van Esch H, Fryns JP, Hamel BC, Sistermans EA, de Vries BB, van Bokhoven H.

Am J Hum Genet. 2006 Aug;79(2):370-7. Epub 2006 Jun 13.

PubMed [citation]

PMID:: 16826528
PMCID:: PMC1559478

Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype.

Kleefstra T, van Zelst-Stams WA, Nillesen WM, Cormier-Daire V, Houge G, Foulds N, van Dooren M, Willemsen MH, Pfundt R, Turner A, Wilson M, McGaughran J, Rauch A, Zenker M, Adam MP, Innes M, Davies C, López AG, Casalone R, Weber A, Brueton LA, Navarro AD, et al.

J Med Genet. 2009 Sep;46(9):598-606. doi: 10.1136/jmg.2008.062950. Epub 2009 Mar 4.

PubMed [citation]

PMID:: 19264732

See all PubMed Citations (5)

Details of each submission

From 3billion, SCV002058486.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported to be associated with EHMT1 related disorder (ClinVar ID: VCV000280682). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Laboratory of Human Genetics, Universidade de São Paulo, SCV002060419.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Brazilian	1	not provided	not provided	research	PubMed (1)

Description

ACMG: PVS1, PS2, PM2, PP3, and PP5

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004458735.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 280682). This variant has not been reported in the literature in individuals affected with EHMT1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg902*) in the EHMT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EHMT1 are known to be pathogenic (PMID: 16826528, 19264732).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Genetics, Children's Clinical University Hospital Latvia, SCV005045819.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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