VCV000003608.7 - ClinVar

NM_024757.5(EHMT1):c.871C>T (p.Arg291Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024757.5(EHMT1):c.871C>T (p.Arg291Ter)

Variation ID: 3608 Accession: VCV000003608.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q34.3 9: 137743418 (GRCh38) [ NCBI UCSC ] 9: 140637870 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 1, 2013	Oct 8, 2024	May 6, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_024757.5:c.871C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_079033.4:p.Arg291Ter	nonsense
NM_001145527.2:c.871C>T	NP_001138999.1:p.Arg291Ter	nonsense
NM_001354259.2:c.778C>T	NP_001341188.1:p.Arg260Ter	nonsense
NM_001354263.2:c.850C>T	NP_001341192.1:p.Arg284Ter	nonsense
NM_001354611.2:c.871C>T	NP_001341540.1:p.Arg291Ter	nonsense
NM_001354612.2:c.778C>T	NP_001341541.1:p.Arg260Ter	nonsense
NC_000009.12:g.137743418C>T
NC_000009.11:g.140637870C>T
NG_011776.1:g.129427C>T

... more HGVS ... less HGVS

Protein change

R260*, R291*, R284*

Other names

Canonical SPDI

NC_000009.12:137743417:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA340104 OMIM: 607001.0004 dbSNP: rs137852714 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
EHMT1		Sufficient evidence for dosage pathogenicity	Little evidence for dosage pathogenicity	GRCh38 GRCh37	2084	2394

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Kleefstra syndrome 1	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	May 6, 2022	RCV000003792.10

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Kleefstra syndrome 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Baylor Genetics Accession: SCV000807330.2 First in ClinVar: Nov 17, 2017 Last updated: Dec 11, 2022	Publications: PubMed (2) PubMed: 25326635‚ 19264732 Comment: This mutation has been previously reported as disease-causing and was found twice in our laboratory in unrelated probands: a 2-year-old male with developmental delay, hypotonia, … (more) This mutation has been previously reported as disease-causing and was found twice in our laboratory in unrelated probands: a 2-year-old male with developmental delay, hypotonia, poor coordination, microcephaly, dysmorphism; & de novo in a 1-year-old male with global delays, dysmorphisms, advanced bone age. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Kleefstra syndrome 1 Affected status: yes Allele origin: de novo	Laboratory of Genetics, Children's Clinical University Hospital Latvia Accession: SCV005045847.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 Comment: de novo	Publications: PubMed (1) PubMed: 39013458
Pathogenic (May 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Kleefstra syndrome 1 Affected status: yes Allele origin: de novo	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: HudsonAlpha-AGHI-WGS Accession: SCV002515841.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: ACMG codes: PVS1_Strong, PS2, PS4M, PM2 Number of individuals with the variant: 1 Clinical Features: Macroglossia (present) , Full cheeks (present) , Micrognathia (present) , Anteverted nares (present) , Eczematoid dermatitis (present) , Global developmental delay (present) , Dysphagia (present) … (more) Macroglossia (present) , Full cheeks (present) , Micrognathia (present) , Anteverted nares (present) , Eczematoid dermatitis (present) , Global developmental delay (present) , Dysphagia (present) , Tracheomalacia (present) (less)
Pathogenic (Sep 01, 2009)	no assertion criteria provided Method: literature only	KLEEFSTRA SYNDROME 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023957.4 First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2020	Publications: PubMed (1) PubMed: 19264732 Comment on evidence: In a 19-year-old man (patient 19) with a phenotype consistent with chromosome 9q subtelomeric deletion syndrome (KLEFS1; 610253), Kleefstra et al. (2009) identified a de … (more) In a 19-year-old man (patient 19) with a phenotype consistent with chromosome 9q subtelomeric deletion syndrome (KLEFS1; 610253), Kleefstra et al. (2009) identified a de novo heterozygous c.778C-T transition (c.778C-T, NM_024757.3) in the EHMT1 gene, resulting in an arg260-to-ter (R260X) substitution, predicted to result in nonsense-mediated mRNA decay. The man had mental retardation, seizures, and characteristic facial abnormalities. (less)
not provided (-)	no classification provided Method: literature only	Kleefstra syndrome 1 Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000087011.2 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 19264732‚ 20945554 BookShelf: NBK47079 BookShelf: NBK47079

Comment:

This mutation has been previously reported as disease-causing and was found twice in our laboratory in unrelated probands: a 2-year-old male with developmental delay, hypotonia, poor coordination, microcephaly, dysmorphism; & de novo in a 1-year-old male with global delays, dysmorphisms, advanced bone age.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome.	Rots D	American journal of human genetics	2024	PMID: 39013458
Kleefstra Syndrome.	Adam MP	-	2023	PMID: 20945554
Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype.	Kleefstra T	Journal of medical genetics	2009	PMID: 19264732

Text-mined citations for rs137852714 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_024757.5(EHMT1):c.871C>T (p.Arg291Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137852714 ...