ClinVar Genomic variation as it relates to human health
NM_001005361.3(DNM2):c.1106G>A (p.Arg369Gln)
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_001005361.3(DNM2):c.1106G>A (p.Arg369Gln)
Variation ID: 7279 Accession: VCV000007279.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 10793833 (GRCh38) [ NCBI UCSC ] 19: 10904509 (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 Apr 4, 2013 Feb 14, 2024 Jun 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001005361.3:c.1106G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001005361.1:p.Arg369Gln missense NM_001005360.3:c.1106G>A NP_001005360.1:p.Arg369Gln missense NM_001005362.3:c.1106G>A NP_001005362.1:p.Arg369Gln missense NM_001190716.2:c.1106G>A NP_001177645.1:p.Arg369Gln missense NM_004945.4:c.1106G>A NP_004936.2:p.Arg369Gln missense NC_000019.10:g.10793833G>A NC_000019.9:g.10904509G>A NG_008792.1:g.80755G>A LRG_238:g.80755G>A LRG_238t1:c.1106G>A LRG_238p1:p.Arg369Gln P50570:p.Arg369Gln - Protein change
- R369Q
- Other names
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- Canonical SPDI
- NC_000019.10:10793832: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
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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
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
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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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DNM2 | - | - |
GRCh38 GRCh37 |
1118 | 1209 |
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
Help
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, single submitter
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- | RCV000007702.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2013 | RCV000145900.6 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 15, 2023 | RCV000701394.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 10, 2021 | RCV001781202.5 |
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
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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Pathogenic
(Feb 08, 2013)
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criteria provided, single submitter
Method: clinical testing
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Myopathy, centronuclear
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000193037.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Pathogenic
(Aug 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002021731.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jun 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease dominant intermediate B
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000830194.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 7279). This missense change has been observed in individuals with centronuclear myopathy and centronuclear myopathy with … (more)
ClinVar contains an entry for this variant (Variation ID: 7279). This missense change has been observed in individuals with centronuclear myopathy and centronuclear myopathy with and without myotonia (PMID: 16227997, 19130742, 24366529, 25501959, 26908122). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 369 of the DNM2 protein (p.Arg369Gln). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNM2 protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg369 amino acid residue in DNM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16227997, 20529869, 20817456, 22613877, 24016602, 25492887, 28676641). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant centronuclear myopathy
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073244.1
First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022 |
Comment:
The missense variant p.R369Q in DNM2 (NM_001005360.3) has been reported in individuals affected with centronuclear myopathy with and without myotonia (Bitoun M et al, 2005; … (more)
The missense variant p.R369Q in DNM2 (NM_001005360.3) has been reported in individuals affected with centronuclear myopathy with and without myotonia (Bitoun M et al, 2005; Chen T et al, 2015; Lin P et al, 2016; Jeub M et al, 2012; Dabby R et al, 2014). The p.R369Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R369Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 369 of DNM2 is conserved in all mammalian species. The nucleotide c.1106 in DNM2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Proximal muscle weakness (present) , Difficulty walking (present) , Difficulty climbing stairs (present) , Lower limb muscle weakness (present) , Lumbar hyperlordosis (present) , Pes … (more)
Proximal muscle weakness (present) , Difficulty walking (present) , Difficulty climbing stairs (present) , Lower limb muscle weakness (present) , Lumbar hyperlordosis (present) , Pes planus (present) (less)
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Pathogenic
(Jun 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease dominant intermediate B
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002526421.1
First in ClinVar: Jun 18, 2022 Last updated: Jun 18, 2022 |
Comment:
The c.1106G>A;p.(Arg369Gln) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 7279; PMID: 28676641; 24366529; 25501959; … (more)
The c.1106G>A;p.(Arg369Gln) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 7279; PMID: 28676641; 24366529; 25501959; 25492887; 24016602) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Dynamin_M) - PM1. This variant is not present in population databases:rs121909089, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported and classified as Pathogenic by ACMG criteria (Clinvar ID: 245905; 7280) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 25501959) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
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Pathogenic
(Nov 01, 2005)
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no assertion criteria provided
Method: literature only
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MYOPATHY, CENTRONUCLEAR, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027903.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In 14 members of a family from French Guyana with autosomal dominant centronuclear myopathy (CNM1; 160150), Bitoun et al. (2005) identified a heterozygous 1106G-A mutation … (more)
In 14 members of a family from French Guyana with autosomal dominant centronuclear myopathy (CNM1; 160150), Bitoun et al. (2005) identified a heterozygous 1106G-A mutation in exon 8 of the DNM2 gene, resulting in an arg369-to-gln (R369Q) substitution. (less)
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Uncertain significance
(Jan 06, 2016)
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no assertion criteria provided
Method: literature only
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Charcot-Marie-Tooth disease dominant intermediate B
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004174665.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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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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Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells. | González-Jamett AM | Scientific reports | 2017 | PMID: 28676641 |
DNM2 mutations in Chinese Han patients with centronuclear myopathy. | Lin P | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2016 | PMID: 26908122 |
Clinical, pathological, and genetic features of dynamin-2-related centronuclear myopathy in China. | Chen T | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2015 | PMID: 25501959 |
The coexistence of dynamin 2 mutation and multiple mitochondrial DNA (mtDNA) deletions in the background of severe cardiomyopathy and centronuclear myopathy. | Gal A | Clinical neuropathology | 2015 | PMID: 25492887 |
Myotonia in DNM2-related centronuclear myopathy. | Dabby R | Journal of neural transmission (Vienna, Austria : 1996) | 2014 | PMID: 24366529 |
Clinicopathological features of centronuclear myopathy in Japanese populations harboring mutations in dynamin 2. | Mori-Yoshimura M | Clinical neurology and neurosurgery | 2012 | PMID: 22613877 |
Sporadic centronuclear myopathy with muscle pseudohypertrophy, neutropenia, and necklace fibers due to a DNM2 mutation. | Liewluck T | Neuromuscular disorders : NMD | 2010 | PMID: 20817456 |
Dynamin 2 mutants linked to centronuclear myopathies form abnormally stable polymers. | Wang L | The Journal of biological chemistry | 2010 | PMID: 20529869 |
Dynamin 2-related centronuclear myopathy: clinical, histological and genetic aspects of further patients and review of the literature. | Jeub M | Clinical neuropathology | 2008 | PMID: 19130742 |
Mutations in dynamin 2 cause dominant centronuclear myopathy. | Bitoun M | Nature genetics | 2005 | PMID: 16227997 |
Text-mined citations for rs121909089 ...
HelpRecord last updated Apr 06, 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.