Variant 2-219425734-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DES
NM_001927.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 3.15

Variant links:

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 links:

DES (HGNC:):

DES links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a region_of_interest Tail (size 57) in uniprot entity DESM_HUMAN there are 27 pathogenic changes around while only 2 benign (93%) in NM_001927.4

PM2

Very rare variant in population databases, with high coverage;

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 [Likely_pathogenic]. Clinvar id is 66402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219425734-C-T is described in Lovd as [Pathogenic]. Variant chr2-219425734-C-T is described in Lovd as [Pathogenic]. Variant chr2-219425734-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 linkuse as main transcript	c.1360C>T	p.Arg454Trp	missense_variant	8/9	ENST00000373960.4	NP_001918.3	P17661Q53SB5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4 linkuse as main transcript	c.1360C>T	p.Arg454Trp	missense_variant	8/9	1	NM_001927.4	ENSP00000363071.3		P17661

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1452416

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721420

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 29, 2021	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 19, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2020	Reported in ClinVar as a pathogenic and likely pathogenic variant (ClinVar Variant ID# 66402; Landrum et al., 2016); 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 (Otten et al., 2010); 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, 20448486, 25557463, 20423733, 25179549, 22403400, 17221859, 27854218, 22153487, 22106715, 18769253, 27810088, 28256728, 29915714, 28611029, 30023281, 28986455, 31912959, 32142595, 31737537, 31402444, 33673806, 32528171) -

Desmin-related myofibrillar myopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	-	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. -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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). 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 DES protein function. 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. -

Primary dilated cardiomyopathy;C0027868:Neuromuscular disease

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 24, 2012

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

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PM2_Supporting+PS4+PM6+PP1+PS3_Supporting+PP4 -

Primary dilated cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Human Genetics, University of Leuven

Feb 09, 2017

ACMG score pathogenic -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

Oct 07, 2014

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2020

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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

CardioboostCm

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.3

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.3

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.66

MVP

0.99

MPC

1.4

ClinPred

1.0

GERP RS

4.5

Varity_R

0.63

gMVP

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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