ClinVar Genomic variation as it relates to human health
NM_000117.3(EMD):c.104AGA[2] (p.Lys37del)
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.
Pathogenic(2); Likely pathogenic(2); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000117.3(EMD):c.104AGA[2] (p.Lys37del)
Variation ID: 1066332 Accession: VCV001066332.17
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: Xq28 X: 154379711-154379713 (GRCh38) [ NCBI UCSC ] X: 153608071-153608073 (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 May 10, 2021 Feb 20, 2024 Oct 31, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000117.3:c.104AGA[2] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000108.1:p.Lys37del inframe deletion NM_000117.3:c.110_112del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000117.2:c.110_112delAGA NC_000023.11:g.154379711AGA[2] NC_000023.10:g.153608071AGA[2] NG_008677.1:g.10276AGA[2] LRG_745:g.10276AGA[2] LRG_745t1:c.110_112del - Protein change
- K37del
- Other names
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- Canonical SPDI
- NC_000023.11:154379710:AGAAGAAGA:AGAAGA
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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
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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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EMD | - | - |
GRCh38 GRCh37 |
531 | 789 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 27, 2023 | RCV001377300.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2023 | RCV001560660.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 16, 2020 | RCV002432060.2 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2023 | RCV003469624.3 |
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
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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
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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
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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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Uncertain significance
(Nov 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002740952.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.110_112delAGA variant (also known as p.K37del) is located in coding exon 2 of the EMD gene. This variant results from an in-frame AGA deletion … (more)
The c.110_112delAGA variant (also known as p.K37del) is located in coding exon 2 of the EMD gene. This variant results from an in-frame AGA deletion at nucleotide positions 110 to 112. This results in the in-frame deletion of a lysine at codon 37, in the LEM domain. The LEM domain is known to play a role in emerin interaction with other proteins involved in genome organization and cell mechanics. Some studies suggest loss of this amino acid residue perturbs the structure of the LEM domain, which is expected to have a deleterious impact on protein function, potentially impairing cellular response to mechanical stress, although the specific mechanism for the clinical impact remains unclear (Samson C et al. FEBS J, 2017 01;284:338-352; Essawy N et al. Cells, 2019 06;8; Ambry internal data). Based on data from gnomAD, this allele has an overall frequency of <0.01% (2/174087) total alleles studied, with 0 hemizygotes observed. The highest observed frequency was <0.01% (1/11589) of African alleles. This deletion has been reported to segregate with disease in at least two families with atrial fibrillation and dilation, with the most severe effects seen in males, although female carriers also demonstrated arrythmia phenotypes tending to be less severe, and developed later in life than in affected male relatives (Ben Yaou R et al. Neurology, 2007 May;68:1883-94; Karst ML et al. J Cardiovasc Electrophysiol, 2008 May;19:510-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious/neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Pathogenic
(Feb 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Emery-Dreifuss muscular dystrophy 1, X-linked
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809735.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Oct 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001783117.4
First in ClinVar: Aug 14, 2021 Last updated: Nov 25, 2023 |
Comment:
In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Functional study suggests that this … (more)
In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Functional study suggests that this variant leads to impaired protein trafficking (PMID: 18266676); however, additional studies are needed to validate the functional effect of this variant in vivo; This variant is associated with the following publications: (PMID: 29540472, 18266676, 32880476, 31024910, 24365856, 36672271, 27960036, Tolmacheva 2023[preprint], 31185657, 17536044) (less)
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Pathogenic
(Apr 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Emery-Dreifuss muscular dystrophy 1, X-linked
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004194607.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Aug 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Emery-Dreifuss muscular dystrophy 1, X-linked
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024485.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Oct 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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X-linked Emery-Dreifuss muscular dystrophy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001574600.4
First in ClinVar: May 10, 2021 Last updated: Feb 20, 2024 |
Comment:
This variant, c.110_112del, results in the deletion of 1 amino acid(s) of the EMD protein (p.Lys37del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.110_112del, results in the deletion of 1 amino acid(s) of the EMD protein (p.Lys37del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs782507902, gnomAD 0.009%). This variant has been observed in individual(s) with EMD-related conditions (PMID: 17536044, 29540472, 32880476). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1066332). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects EMD function (PMID: 31185657). 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. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Implications of Genetic Testing in Dilated Cardiomyopathy. | Verdonschot JAJ | Circulation. Genomic and precision medicine | 2020 | PMID: 32880476 |
An Emerin LEM-Domain Mutation Impairs Cell Response to Mechanical Stress. | Essawy N | Cells | 2019 | PMID: 31185657 |
Prevalence of Pathogenic Gene Mutations and Prognosis Do Not Differ in Isolated Left Ventricular Dysfunction Compared With Dilated Cardiomyopathy. | Hazebroek MR | Circulation. Heart failure | 2018 | PMID: 29540472 |
Emerin self-assembly mechanism: role of the LEM domain. | Samson C | The FEBS journal | 2017 | PMID: 27960036 |
X-linked nonsyndromic sinus node dysfunction and atrial fibrillation caused by emerin mutation. | Karst ML | Journal of cardiovascular electrophysiology | 2008 | PMID: 18266676 |
Multitissular involvement in a family with LMNA and EMD mutations: Role of digenic mechanism? | Ben Yaou R | Neurology | 2007 | PMID: 17536044 |
Text-mined citations for rs782507902 ...
HelpRecord last updated Mar 17, 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.