ClinVar Genomic variation as it relates to human health
NM_006709.5(EHMT2):c.3229G>T (p.Ala1077Ser)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006709.5(EHMT2):c.3229G>T (p.Ala1077Ser)
Variation ID: 2687731 Accession: VCV002687731.1
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p21.33 6: 31881061 (GRCh38) [ NCBI UCSC ] 6: 31848838 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jan 26, 2024 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006709.5:c.3229G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006700.3:p.Ala1077Ser missense NM_001289413.2:c.3298G>T NP_001276342.1:p.Ala1100Ser missense NM_001318833.2:c.2623G>T NP_001305762.1:p.Ala875Ser missense NM_001363689.2:c.3400G>T NP_001350618.1:p.Ala1134Ser missense NM_001395160.1:c.3250G>T NP_001382089.1:p.Ala1084Ser missense NM_001395161.1:c.3166G>T NP_001382090.1:p.Ala1056Ser missense NM_001395162.1:c.3151G>T NP_001382091.1:p.Ala1051Ser missense NM_001395163.1:c.3148G>T NP_001382092.1:p.Ala1050Ser missense NM_001395164.1:c.3124G>T NP_001382093.1:p.Ala1042Ser missense NM_001395165.1:c.2971G>T NP_001382094.1:p.Ala991Ser missense NM_025256.7:c.3127G>T NP_079532.5:p.Ala1043Ser missense NR_174947.1:n.814C>A non-coding transcript variant NC_000006.12:g.31881061C>A NC_000006.11:g.31848838C>A NG_023058.1:g.2986G>T - Protein change
- A1042S, A1043S, A1050S, A1051S, A1056S, A1077S, A1084S, A1100S, A1134S, A875S, A991S
- Other names
- G9A
- Canonical SPDI
- NC_000006.12:31881060:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- loss_of_function_variant Sequence Ontology [SO:0002054]
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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EHMT2 | - | - |
GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37 |
47 | 61 | |
EHMT2-AS1 | - | - | - |
GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 |
- | 21 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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- | RCV003484975.1 |
Submissions - Germline
Classification
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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
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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. |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing, in vitro
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Kleefstra-like syndrome
(Sporadic)
Affected status: yes, not applicable
Allele origin:
de novo,
not applicable
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Spanish Undiagnosed Rare Disease Program-IIER, Instituto de Salud Carlos III
Accession: SCV004231847.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Pediatric patient with a Kleefstra-overlapping phenotype and a single base de novo substitution in EHMT2 that causes the amino acid change p.Ala1077Ser in the catalytic … (more)
Pediatric patient with a Kleefstra-overlapping phenotype and a single base de novo substitution in EHMT2 that causes the amino acid change p.Ala1077Ser in the catalytic SET domain. This change causes a reduction in the affinity of the catalytic domain for histone H3 tail and in the activity of the enzyme by three- to five-fold. DNA methylation, histone methylation and gene expression profiles suggest a significant overlap between the EHMT2 p.Ala1077Ser variant and Kleefstra Syndrome. (less)
Observation 1:
Clinical Features:
Flat face (present) , Inguinal hernia (present) , Nephrocalcinosis (present) , Abnormality of the mouth (present) , Brachycephaly (present) , Epicanthus (present) , Smooth philtrum … (more)
Flat face (present) , Inguinal hernia (present) , Nephrocalcinosis (present) , Abnormality of the mouth (present) , Brachycephaly (present) , Epicanthus (present) , Smooth philtrum (present) , Upslanted palpebral fissure (present) , Motor stereotypies (present) , Intellectual disability (present) , Global developmental delay (present) , Motor delay (present) , Neonatal hypotonia (present) , Plagiocephaly (present) , Coarctation of aorta (present) , Low posterior hairline (present) , Language disorder (present) , Scoliosis (present) , Equinovarus deformity (present) , Bilateral cryptorchidism (present) , Short palpebral fissure (present) (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Europe
Observation 2:
Method: Histone methyltransferase assays were performed using the fluorescence-based assay SAM Methyltransferase Assay SAMfluoro™ from G-Biosciences that detects the formation of resorufin over time as a result of the methyltransferase reaction. Assays were performed using 250, 500 or 1000 ng of His-tagged WT or p.Ala1077Ser EHMT2 catalytic domains (expressed and purified in E. coli) and 2.5 µg of recombinant histone H3 following the manufacturer instructions. Cumulative reads were measured every minute for 45 minutes. Specific activity was calculated using a resorufin standard.
Result:
Change p.Ala1077Ser causes a decrease in the catalytic activity of the enzyme by three- to five-fold
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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loss_of_function_variant
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Spanish Undiagnosed Rare Disease Program-IIER, Instituto de Salud Carlos III
Accession: SCV004231847.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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- | - | - | - | DOI: 10.1101/2024.01.10.24300997 |
Text-mined citations for this variant ...
HelpRecord last updated Feb 14, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.