rs587783595
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001005361.3(DNM2):c.1565G>A(p.Arg522His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R522C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001005361.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNM2 | NM_001005361.3 | c.1565G>A | p.Arg522His | missense_variant | 15/21 | ENST00000389253.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNM2 | ENST00000389253.9 | c.1565G>A | p.Arg522His | missense_variant | 15/21 | 5 | NM_001005361.3 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1447522Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 719044
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 26, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 04, 2019 | Reported in association with centronuclear myopathy in published literature (Susman et al., 2010; Chen et al., 2015); Published functional studies demonstrate that R522H impairs protein interaction with microtubules and results in reduced clathrin-mediated endocytosis (Koutsopoulos et al., 2011; Bragato et al., 2016); Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; A diffferent missense change at this residue (R522C) has been reported in the Human Gene Mutation Database in association with CNM (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 26908122, 22096584, 26842864, 20227276, 25501959, 27363342, 29105112, 28357410, 31017801, 32826616) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2018 | - - |
Autosomal dominant centronuclear myopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This mutation has been previously reported as disease-causing and was found once in our laboratory de novo in a 16-year-old female with centronuclear myopathy on muscle biopsy; proximal muscle weakness, facial weakness, fatigue, varus foot, waddling gait. - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | May 19, 2022 | - - |
Charcot-Marie-Tooth disease dominant intermediate B Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 522 of the DNM2 protein (p.Arg522His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with centronuclear myopathy (PMID: 20227276, 22396310, 24465259, 25501959, 25957634, 26908122). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 158514). 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. Experimental studies have shown that this missense change affects DNM2 function (PMID: 22096584, 26842864). For these reasons, this variant has been classified as Pathogenic. - |
See cases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Aug 20, 2020 | ACMG classification criteria: PS4, PM2, PM6, PP1 - |
Centronuclear myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at