chr2-219421532-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_001927.4(DES):c.1216C>T(p.Arg406Trp) variant causes a missense change involving the alteration of a non-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 (★★).
Frequency
Consequence
NM_001927.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DES | ENST00000373960.4 | c.1216C>T | p.Arg406Trp | missense_variant | Exon 6 of 9 | 1 | NM_001927.4 | ENSP00000363071.3 | ||
| DES | ENST00000477226.6 | n.690C>T | non_coding_transcript_exon_variant | Exon 5 of 8 | 4 | |||||
| DES | ENST00000492726.1 | n.611C>T | non_coding_transcript_exon_variant | Exon 5 of 6 | 4 | |||||
| DES | ENST00000683013.1 | n.604C>T | non_coding_transcript_exon_variant | Exon 4 of 7 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 33
GnomAD4 genome
ClinVar
Submissions by phenotype
Desmin-related myofibrillar myopathy Pathogenic:7
The p.Arg406Trp variant in DES is absent from large populations sequenced by the Exome Aggregation Consortium (exac.broadinstitute.org/) but has been reported i n at least 5 individuals with clinical features of desminopathies, including con duction system disease +/-cardiomyopathy (DCM and RCM) and skeletal myopathy (sa me individuals reported in multiple papers; Dalakas 2000, Park 2000, Dagvadirj 2 004, Olive 2004, Wahbi 2012). In at least least 4 individuals the variant had oc curred de novo (paternity confirmed; same individuals reported in multiple paper s; Dalakas 2000, Park 2000, Dagvadirj 2004, Olive 2004). In vitro functional stu dies provide some evidence that the p.Arg406Trp variant impacts protein function (Park 2000, Chourbagi 2011). However, these types of assays sometimes do not ac curately represent biological function. In summary, this variant meets our crite ria to be classified as pathogenic for desminopathy with cardiac and skeletal my opathy involvement in an autosomal dominant manner (http://www.partners.org/pers onalizedmedicine/LMM) based upon absence from the general population and de novo occurrence. -
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The missense c.1216C>Tp.Arg406Trp variant in DES gene has been reported previously in heterozygous state in individuals affected with Desminopathy, a familial or sporadic cardiac and skeletal muscular dystrophy Dagvadorj et al., 2004. Experimental studies have shown that this missense change affects DES function Joanne et al., 2013. This variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submitters. In at least one individual the variant was observed to be de novo. The amino acid Arg at position 406 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg406Trp in DES is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic. -
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 406 of the DES protein (p.Arg406Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with desmin myopathy (PMID: 10717012, 10905661, 14991347). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 16826). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DES protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects DES function (PMID: 21262226, 23425003). For these reasons, this variant has been classified as Pathogenic. -
PM2_supporting: This variant is absent from gnomAD v4.0 (adequate coverage >20x confirmed). PP3_moderate: REVEL score is 0.807. PM1 met: This variant occurs in exon 6 which encodes the C-terminal half of the coil 2 domain. Although disease-causing mutations spread over the entire desmin gene, they significantly cluster in exon 6. PS3_Supporting: functional studies provide supportive evidence that this variant has a damaging effect on the gene or gene product PS2_Moderate: Max 1 point awarded for 2 probands with de novo observations (paternity confirmed) and phenotype consistent with gene but not highly specific and high genetic heterogeneity. PS4 met: >=10 unrelated probands with consistent phenotype for disorder. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases. -
not provided Pathogenic:2Other:1
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Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate abnormal filament assembly, in addition to microscopic analysis of cardiac and skeletal muscle revealing desmin-positive protein aggregates (Park et al., 2000; Chourbagi et al., 2011; Herrmann et al., 2020; Kubnek et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10717012, 35653365, 35626289, 35239206, 26807690, 10905661, 14991347, 27854218, 33673806, 32528171, 34712946, 32235386, 21262226, 33023321, 16376610) -
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Cardiomyopathy Pathogenic:1
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Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1
This sequence change in DES is predicted to replace arginine with tryptophan at codon 406, p.(Arg406Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the intermediate filament rod domain. There is a large physicochemical difference between arginine and tryptophan. This variant is absent from gnomAD v2.1 and v3.1. This variant is frequently de novo, and has been identified as a de novo occurrence with confirmed parental relationships in at least four individuals with a severe and early-onset cardiomyopathy with/without myopathy. All reported individuals had muscle biopsy features consistent with a desmin myopathy (PMID: 10717012, 10905661, 14991347). A knock-in mouse-model of the orthologous variant developed a phenotype consistent with desmin myopathy, including desmin-positive protein aggregate pathology in skeletal muscle tissue (PMID: 33023321). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PS2_VeryStrong, PS3, PM2_Supporting, PP3. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at