chr2-219421532-C-T

Position:

• chr2-219421532-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000373960.4(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R406Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DES ENST00000373960.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 0.323

Genes affected

DES (HGNC:2770): (desmin) This gene encodes a muscle-specific class III intermediate filament. Homopolymers of this protein form a stable intracytoplasmic filamentous network connecting myofibrils to each other and to the plasma membrane. Mutations in this gene are associated with desmin-related myopathy, a familial cardiac and skeletal myopathy (CSM), and with distal myopathies. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in ENST00000373960.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-219421533-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2109936.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 2-219421532-C-T is Pathogenic according to our data. Variant chr2-219421532-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219421532-C-T is described in Lovd as [Pathogenic]. Variant chr2-219421532-C-T is described in Lovd as [Pathogenic]. Variant chr2-219421532-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DES	NM_001927.4	c.1216C>T	p.Arg406Trp	missense_variant	6/9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.1216C>T	p.Arg406Trp	missense_variant	6/9	1	NM_001927.4	ENSP00000363071	P1
DES	ENST00000477226.6	n.690C>T		non_coding_transcript_exon_variant	5/8	4
DES	ENST00000492726.1	n.611C>T		non_coding_transcript_exon_variant	5/6	4
DES	ENST00000683013.1	n.604C>T		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Desmin-related myofibrillar myopathy Pathogenic:7

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2000	- -
Pathogenic, criteria provided, single submitter	research	Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	May 22, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 20, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2023	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). 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) performed at Invitae 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 11, 2015	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. -
Likely pathogenic, criteria provided, single submitter	research	Center for Genetic Medicine Research, Children's National Medical Center	Dec 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2023	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) -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2016	- -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Mar 30, 2023

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. -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 04, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
MutationTaster	Benign	0.99	A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.97		Loss of disorder (P = 0.0509);
MVP		0.98
MPC		1.5
ClinPred		1.0	D
GERP RS		2.1
Varity_R		0.82
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121913003; hg19: chr2-220286254; COSMIC: COSV105297244; COSMIC: COSV105297244;