ClinVar Genomic variation as it relates to human health
NM_004408.4(DNM1):c.1335+1638G>A
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_004408.4(DNM1):c.1335+1638G>A
Variation ID: 429529 Accession: VCV000429529.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.11 9: 128226027 (GRCh38) [ NCBI UCSC ] 9: 130988306 (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 Jul 2, 2017 May 6, 2023 May 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004408.4:c.1335+1638G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001005336.3:c.1335+1638G>A intron variant NM_001288737.2:c.1197-8G>A intron variant NM_001288738.2:c.1197-8G>A intron variant NM_001288739.2:c.1197-8G>A intron variant NC_000009.12:g.128226027G>A NC_000009.11:g.130988306G>A NG_029726.1:g.27644G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000009.12:128226026:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- probably has functional consequence
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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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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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DNM1 | - | - |
GRCh38 GRCh37 |
605 | 891 |
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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Aug 23, 2022 | RCV000492949.5 | |
not provided (1) |
no classification provided
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- | RCV001824808.1 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 2, 2023 | RCV002286525.5 |
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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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 31
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002574901.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Age: 0-9 years
Sex: male
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Pathogenic
(Aug 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV003802785.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
Comment:
The DNM1 c.1197-8G>A variant occurs in a splice region and results in the substitution of a guanine at nucleotide position c.1197-8 with an adenine. The … (more)
The DNM1 c.1197-8G>A variant occurs in a splice region and results in the substitution of a guanine at nucleotide position c.1197-8 with an adenine. The variant is 8 bases upstream of exon 10a which is present in isoforms of DNM1 predominant in the brain, including the NM_001288739.1 transcript (PMID: 36413998). Three studies have reported the c.1197-8G>A variant in a presumed de novo state in ten individuals with developmental and epileptic encephalopathy (PMID: 30097719; PMID: 32909139;PMID: 36413998). This variant has been shown by minigene expression studies to result in the insertion of two amino acid residues (cystine and arginine) between arginine 399 and threonine 400. Structural analysis of the variant predicts that the insertion of two amino acid residues results in disruption of tetramerization, a process required to activate GTPase activity. This evidence suggests a dominant negative effect of the variant. Neuropathology analysis of brain tissue from an affected individual who was heterozygous for the variant showed abnormal vesicular fission and vesicle trafficking deficiency (PMID: 36413998). The c.1197-8G>A variant is not reported in the Genome Aggregation Database version 2.1.1 or 3.1.2. Based on the available evidence, the c.1197-8G>A variant is classified as pathogenic for developmental and epileptic encephalopathy. (less)
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Pathogenic
(May 26, 2022)
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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: SCV000582119.5
First in ClinVar: Jul 02, 2017 Last updated: Mar 04, 2023 |
Comment:
Located in an alternative transcript of the gene; Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This … (more)
Located in an alternative transcript of the gene; Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32909139, 30097719, 27535533) (less)
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Pathogenic
(May 02, 2023)
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criteria provided, single submitter
Method: curation
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Developmental and epileptic encephalopathy, 31
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003922137.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
The heterozygous c.1197-8G>A variant in DNM1 was identified by our study in one individual with epileptic encephalopathy, brain atrophy, optic atrophy, and microcephaly. Trio exome … (more)
The heterozygous c.1197-8G>A variant in DNM1 was identified by our study in one individual with epileptic encephalopathy, brain atrophy, optic atrophy, and microcephaly. Trio exome analysis showed this variant to be de novo. The c.1197-8G>A variant in DNM1 has been previously reported in 10 unrelated individuals with developmental and epileptic encephalopathy 31 (PMID: 36413998, PMID: 30097719, PMID: 32909139). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 10 individuals with confirmed paternity and maternity (PMID: 36413998, PMID: 30097719, PMID: 32909139). This variant has also been reported in ClinVar (Variation ID: 429529) and has been interpreted as pathogenic by GeneDx and as likely pathogenic by Kasturba Medical College, Manipal, Manipal Academy of Higher Education (PMID: 36413998, PMID: 30097719, PMID: 32909139). This variant was absent from large population studies. In vitro functional studies provide some evidence that the variant may impact protein function, with minigene assays in HEK293 cells showing altered splicing with creation of a novel splice site 6bp upstream of the canonical splice site of exon 10 and in-frame insertion of 2 amino acids (a cysteine and an arginine (CR) in the beginning of exon 10, which was predicted by structural modeling to impede DNM1 protein oligomerization-induced GTPase activation (PMID: 36413998). However, these types of assays may not accurately represent biological function. This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant developmental and epileptic encephalopathy 31. ACMG/AMP Criteria applied: PS2_VeryStrong, PS3_Supporting, PS4, PM2_Supporting (Richards 2015). (less)
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Pathogenic
(Apr 26, 2023)
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no assertion criteria provided
Method: literature only
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DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 31A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV003920653.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment on evidence:
In 8 unrelated patients with developmental and epileptic encephalopathy-31A (DEE31A; 616346), Parthasarathy et al. (2022) identified de novo heterozygosity for a c.1197-8G-A transition (c.1197-8G-A, NM_001288739.1) … (more)
In 8 unrelated patients with developmental and epileptic encephalopathy-31A (DEE31A; 616346), Parthasarathy et al. (2022) identified de novo heterozygosity for a c.1197-8G-A transition (c.1197-8G-A, NM_001288739.1) in the DNM1 gene, resulting in a splicing abnormality. The mutation was identified by whole-exome sequencing or sequencing of a panel of genes. A minigene assay evaluating splicing of DNM1 with the c.1197-8G-A mutation showed that it resulted in creation of a new splice site and insertion of 2 amino acids in exon 10 between R399 and T400. This was predicted to result in disrupted GTPase activation of DNM1 oligomers. Examination of brain tissue from one of the patients demonstrated decreased neuronal density in gray matter including the thalamus, decreased density of axons in the white matter, and synaptic dystrophy, particularly in the globus pallidus. Ultrastructural studies showed abnormal vesicles, consistent with a vesicular trafficking defect. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Developmental and epileptic encephalopathy, 1
Affected status: unknown
Allele origin:
de novo
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GenomeConnect, ClinGen
Accession: SCV002075028.1
First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022 |
Comment:
Variant interpreted as Pathogenic and reported on 01-19-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 01-19-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Cognitive impairment (present) , EEG abnormality (present) , Encephalopathy (present) , Hypertonia (present) , Generalized hypotonia (present) , Seizure (present) , Abnormal muscle physiology (present) … (more)
Cognitive impairment (present) , EEG abnormality (present) , Encephalopathy (present) , Hypertonia (present) , Generalized hypotonia (present) , Seizure (present) , Abnormal muscle physiology (present) , Abnormal morphology of the pelvis musculature (present) , Feeding difficulties (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2021-01-19
Testing laboratory interpretation: Pathogenic
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Germline Functional Evidence
Functional
Help
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
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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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probably has functional consequence
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002574901.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism. | Parthasarathy S | American journal of human genetics | 2022 | PMID: 36413998 |
Severe DNM1 encephalopathy with dysmyelination due to recurrent splice site pathogenic variant. | Sahly AN | Human genetics | 2020 | PMID: 32909139 |
Genome-wide investigation of an ID cohort reveals de novo 3'UTR variants affecting gene expression. | Devanna P | Human genetics | 2018 | PMID: 30097719 |
Text-mined citations for rs747079285 ...
HelpRecord last updated Mar 30, 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.