Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31623504, 23232695, 30370152)
ClinVar Genomic variation as it relates to human health
NM_024757.5(EHMT1):c.2712+1G>A
Germline
Classification
Help
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.
(10)
Help
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
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024757.5(EHMT1):c.2712+1G>A
Variation ID: 374034 Accession: VCV000374034.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.3 9: 137800985 (GRCh38) [ NCBI UCSC ] 9: 140695437 (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 13, 2017 Oct 20, 2024 Nov 17, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024757.5:c.2712+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001354263.2:c.2691+1G>A splice donor NC_000009.12:g.137800985G>A NC_000009.11:g.140695437G>A NG_011776.1:g.186994G>A - Protein change
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- Other names
- -
- Canonical SPDI
- NC_000009.12:137800984:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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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
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
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| 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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 21, 2015 | RCV000415193.3 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2023 | RCV000521222.20 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Nov 17, 2023 | RCV001007951.10 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Oct 21, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Abnormal facial shape
Difficulty walking Global developmental delay Polymicrogyria
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492728.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
|
|
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Pathogenic
(Mar 21, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Kleefstra syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Genomic Medicine Lab, University of California San Francisco
Study: CSER
Accession: SCV001167665.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Sex: female
Secondary finding: no
|
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Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447629.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Global developmental delay (present) , Short stature (present) , Abnormal heart morphology (present)
Sex: male
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|
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Pathogenic
(Feb 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000617429.5
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is … (more)
Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31623504, 23232695, 30370152) (less)
|
|
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Pathogenic
(May 26, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Kleefstra syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557528.2
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein. The substitution at this canonical splice site has been shown to result in a frameshift leading to a predicted loss of protein function through NMD (PMID 23232695) (intron 18 of 26). (P) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. The substitution at this canonical splice site has also been shown to result in skipping of exon 18 (PMID 23232695). (P) 0301 - Variant is absent from gnomAD. (P) 0401 - Variant is located in a gene associated with a severe early onset DOMINANT condition that is INTOLERANT to loss-of-function variants. (P) 0505 - Abnormal splicing is predicted by in silico tools and nucleotide is highly conserved. (P) 0604 - Variant is not located in an established domain, motif or hotspot. (N) 0704 - Comparable variant in relevant codon/region has low previous evidence for pathogenicity. A different variant in the same splice site, c.2712+1G>C, has also been previously reported in a clinical case (ClinVar). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in multiple patients with Kleefstra syndrome, and was shown to be de novo on one occasion (ClinVar; PMID: 23232695, 30370152). (P) 1007 - No published functional evidence has been identified for this variant. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Pathogenic
(Nov 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Kleefstra syndrome 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004273399.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 18 of the EHMT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 18 of the EHMT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EHMT1 are known to be pathogenic (PMID: 16826528, 19264732). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Kleefstra syndrome (PMID: 23232695, 30370152, 31623504). ClinVar contains an entry for this variant (Variation ID: 374034). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
|
criteria provided, single submitter
Method: curation
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Kleefstra syndrome 1
Affected status: yes
Allele origin:
de novo
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Laboratory of Genetics, Children's Clinical University Hospital Latvia
Accession: SCV005045835.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024
Comment:
de novo
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|
|
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Pathogenic
(Mar 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV003917752.13
First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024 |
Comment:
EHMT1: PVS1, PS2, PM2
Number of individuals with the variant: 1
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Pathogenic
(Jan 27, 2017)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV000778239.1
First in ClinVar: Jun 02, 2018 Last updated: Jun 02, 2018 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Kleefstra syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001984754.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
|
Comment:
Comment:
Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein. The substitution at this canonical splice site has been shown to result in a frameshift leading to a predicted loss of protein function through NMD (PMID 23232695) (intron 18 of 26). (P) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. The substitution at this canonical splice site has also been shown to result in skipping of exon 18 (PMID 23232695). (P) 0301 - Variant is absent from gnomAD. (P) 0401 - Variant is located in a gene associated with a severe early onset DOMINANT condition that is INTOLERANT to loss-of-function variants. (P) 0505 - Abnormal splicing is predicted by in silico tools and nucleotide is highly conserved. (P) 0604 - Variant is not located in an established domain, motif or hotspot. (N) 0704 - Comparable variant in relevant codon/region has low previous evidence for pathogenicity. A different variant in the same splice site, c.2712+1G>C, has also been previously reported in a clinical case (ClinVar). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in multiple patients with Kleefstra syndrome, and was shown to be de novo on one occasion (ClinVar; PMID: 23232695, 30370152). (P) 1007 - No published functional evidence has been identified for this variant. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Comment:
This sequence change affects a donor splice site in intron 18 of the EHMT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EHMT1 are known to be pathogenic (PMID: 16826528, 19264732). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Kleefstra syndrome (PMID: 23232695, 30370152, 31623504). ClinVar contains an entry for this variant (Variation ID: 374034). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
EHMT1: PVS1, PS2, PM2
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:
Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31623504, 23232695, 30370152)
Comment:
Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein. The substitution at this canonical splice site has been shown to result in a frameshift leading to a predicted loss of protein function through NMD (PMID 23232695) (intron 18 of 26). (P) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. The substitution at this canonical splice site has also been shown to result in skipping of exon 18 (PMID 23232695). (P) 0301 - Variant is absent from gnomAD. (P) 0401 - Variant is located in a gene associated with a severe early onset DOMINANT condition that is INTOLERANT to loss-of-function variants. (P) 0505 - Abnormal splicing is predicted by in silico tools and nucleotide is highly conserved. (P) 0604 - Variant is not located in an established domain, motif or hotspot. (N) 0704 - Comparable variant in relevant codon/region has low previous evidence for pathogenicity. A different variant in the same splice site, c.2712+1G>C, has also been previously reported in a clinical case (ClinVar). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in multiple patients with Kleefstra syndrome, and was shown to be de novo on one occasion (ClinVar; PMID: 23232695, 30370152). (P) 1007 - No published functional evidence has been identified for this variant. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Comment:
This sequence change affects a donor splice site in intron 18 of the EHMT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EHMT1 are known to be pathogenic (PMID: 16826528, 19264732). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Kleefstra syndrome (PMID: 23232695, 30370152, 31623504). ClinVar contains an entry for this variant (Variation ID: 374034). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
EHMT1: PVS1, PS2, PM2
Citations for germline classification of this variant
Help| 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 |
| Diagnostic and Clinical Utility of Clinical Exome Sequencing in Children With Moderate and Severe Global Developmental Delay / Intellectual Disability. | Stojanovic JR | Journal of child neurology | 2020 | PMID: 31623504 |
| Hypogonadotropic Hypogonadism and Kleefstra Syndrome due to a Pathogenic Variant in the EHMT1 Gene: An Underrecognized Association. | Torga AP | Case reports in endocrinology | 2018 | PMID: 30370152 |
| A mosaic maternal splice donor mutation in the EHMT1 gene leads to aberrant transcripts and to Kleefstra syndrome in the offspring. | Rump A | European journal of human genetics : EJHG | 2013 | PMID: 23232695 |
| 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 |
| Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. | Kleefstra T | American journal of human genetics | 2006 | PMID: 16826528 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs1057518849 ...
HelpThese 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 20, 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.