2-219425734-C-T

Variant names:

• chr2-219425734-C-T
• rs267607490
• NM_001927.4:c.1360C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001927.4(DES):​c.1360C>T​(p.Arg454Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 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. R454Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 3.15
• Publications: 32 publications found

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]

DES Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1I

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• myofibrillar myopathy 1

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• atrioventricular block

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neurogenic scapuloperoneal syndrome, Kaeser type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000234638 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_001927.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 1.7729 (below the threshold of 3.09). Trascript score misZ: 0.36303 (below the threshold of 3.09). GenCC associations: The gene is linked to myofibrillar myopathy 1, dilated cardiomyopathy 1I, atrioventricular block, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, familial isolated dilated cardiomyopathy, neurogenic scapuloperoneal syndrome, Kaeser type.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 2-219425734-C-T is Pathogenic according to our data. Variant chr2-219425734-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 66402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DES	NM_001927.4	c.1360C>T	p.Arg454Trp	missense_variant	Exon 8 of 9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4	c.1360C>T	p.Arg454Trp	missense_variant	Exon 8 of 9	1	NM_001927.4	ENSP00000363071.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 234706 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452416 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721420

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.00 AC: 0 AN: 43044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25786

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39454

South Asian (SAS) AF: 0.00 AC: 0 AN: 84184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107732

Other (OTH) AF: 0.00 AC: 0 AN: 60126

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Other:1

Aug 29, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Feb 12, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Immunohistochemistry on myocardial samples showed severely disrupted desmin protein distribution and a marked decrease in connexin-43, desmoplakin, and PKP2 signals at the intercalated discs (PMID: 20423733); 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: 23349452, 39657141, 25557463, 37082475, 35838873, 36243179, 36357925, 25179549, 22403400, 17221859, 27854218, 22153487, 22106715, 18769253, 27810088, 28256728, 29915714, 28611029, 30023281, 28986455, 31912959, 32142595, 31402444, 33673806, 32528171, 32235386, 35456383, 20448486, 38702926, 38771229, 34315782, LiL2024[Article], 26807690, 33906374, 20423733, 35653365, 31737537, 20171226)

Jul 19, 2016

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 24, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Desmin-related myofibrillar myopathy Pathogenic:4

Dec 01, 2015

Center for Genetic Medicine Research, Children's National Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variation in exon 8 of the DES gene that results in the amino acid substitution of Tryptophan for Arginine at codon 454 was detected . The observed variation has previously been reported in patients affected with myofibrillar myopathy. The p.Arg454Trp variant has not been reported in 1000 genomes and gnomAD databases. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT. The reference codon is conserved across species. This variant has been previously reported in patients with early distal myopathy and cardiomyopathy (PMID: 37082475). In summary, the variant meets our criteria to be classified as pathogenic.

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 454 of the DES protein (p.Arg454Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant DES-related conditions (PMID: 17221859, 20423733, 22106715, 22153487, 23349452, 25557463, 27854218). 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: 66402). 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: 17221859, 20171226, 20448486). For these reasons, this variant has been classified as Pathogenic.

Nov 03, 2023

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1,PM2,PP3,PP5, PP2?,PS3

Cardiovascular phenotype Pathogenic:2

May 05, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R454W pathogenic mutation (also known as c.1360C>T), located in coding exon 8 of the DES gene, results from a C to T substitution at nucleotide position 1360. The arginine at codon 454 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the tail domain. This alteration was first reported in a subject with suspected hypertrophic cardiomyopathy (HCM) and muscle weakness who also carried a missense alteration in MYOT (Bär H et al. Hum Mutat, 2007 Apr;28:374-86). This alteration has also been reported in 2 sets of siblings with arrhythmogenic right ventricular cardiomyopathy (ARVC), including one set who also had muscle weakness (Otten E et al. Heart Rhythm, 2010 Aug;7:1058-64; Weihl CC et al. Neuromuscul Disord, 2015 Mar;25:199-206). In addition, this alteration has been reported as de novo in several cases (Bär H et al. Hum Mutat, 2007 Apr;28:374-86; Ackerman JP et al. Mayo Clin Proc, 2016 Oct; Oomen AWGJ et al. HeartRhythm Case Rep, 2018 Jul;4:318-323; Gearhart AS et al. HeartRhythm Case Rep, 2018 May;4:184-186). Functional studies also suggest this alteration has an impact on filament formation (Bär H et al. Hum Mutat, 2007 Apr;28:374-86; Levin J et al. J Neuropathol Exp Neurol, 2010 Apr;69:415-24). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Aug 23, 2024

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PS4, PS3_mod, PM2, PP1_mod, PP3

Primary dilated cardiomyopathy;C0027868:Neuromuscular disease Pathogenic:1

May 24, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg454Trp variant in DES has been identified in 1 individual with HCM and mu scle weakness and in 2 siblings with AV Block and cardiac hypertrophy that progr essed to heart failure (Bar 2007, Otten 2010). This variant was also absent from 600 chromosomes and reportedly occurred de novo in the individual with HCM (Bar 2007). Functional studies demonstrated an effect on filament formation (Bar 200 7, Levin 2010). Arginine (Arg) at position 454 is highly conserved in evolution and computational analyses (PolyPhen2 and SIFT) suggest that this variant may im pact the protein, though this information is not predictive enough to determine a pathogenic role. Desmin variants have been described in patients with cardiomy opathy +/- myopathy (desminopathies; Goldfarb 2009, van Spaendonck-Zwarts 2010). In summary, this data supports that the Arg454Trp variant is likely pathogenic, though is needed to fully establish its pathogenicity.

Desmin-related myofibrillar myopathy;C1858154:Dilated cardiomyopathy 1I;C1867005:Neurogenic scapuloperoneal syndrome, Kaeser type Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Assumed de novo, but without confirmation of paternity and maternity.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.

Primary dilated cardiomyopathy Pathogenic:1

Feb 09, 2017

Center for Human Genetics, University of Leuven

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG score pathogenic

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Oct 07, 2014

Blueprint Genetics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		3.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.66
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.63
gMVP		0.93
Mutation Taster		=16/84	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs267607490; hg19: chr2-220290456; COSMIC: COSV64660545; COSMIC: COSV64660545;