chr19-10823862-C-T
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001005361.3(DNM2):c.1856C>T(p.Ser619Leu) 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. 13/21 in silico tools predict a damaging 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. S619W) has been classified as 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.1856C>T | p.Ser619Leu | missense_variant | 17/21 | ENST00000389253.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNM2 | ENST00000389253.9 | c.1856C>T | p.Ser619Leu | missense_variant | 17/21 | 5 | NM_001005361.3 | A1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Autosomal dominant centronuclear myopathy Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | NeuroMeGen, Hospital Clinico Santiago de Compostela | Oct 08, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
Charcot-Marie-Tooth disease dominant intermediate B Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 619 of the DNM2 protein (p.Ser619Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with centronuclear myopathy and is associated with severe neonatal hypotonia (PMID: 17932957, 20227276, 22396310). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7285). 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: 20700106, 23338057, 24135484, 26199319). This variant disrupts the p.Ser619 amino acid residue in DNM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17932957, 20700106, 22396310, 25957634). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
Severe X-linked myotubular myopathy Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2007 | - - |
not provided Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Dec 12, 2016 | - - |
Charcot-Marie-Tooth disease dominant intermediate B;C4551952:Autosomal dominant centronuclear myopathy;C4706410:Fetal akinesia-cerebral and retinal hemorrhage syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 20, 2021 | - - |
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