NM_001927.4:c.1360C>T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000321547: 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); SCV000552172: Experimental studies have shown that this missense change affects DES function (PMID:17221859, 20171226, 20448486).; SCV000204710: Functional studies demonstrated an effect on filament formation (Bar 2007, Levin 2010).; SCV002699622: 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).; SCV005418245: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."". 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• myofibrillar myopathy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• myofibrillar myopathy 1

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

  Inheritance: AR, AD 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 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000321547: 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); SCV000552172: Experimental studies have shown that this missense change affects DES function (PMID: 17221859, 20171226, 20448486).; SCV000204710: Functional studies demonstrated an effect on filament formation (Bar 2007, Levin 2010).; SCV002699622: 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).; SCV005418245: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 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, atrioventricular block, arrhythmogenic right ventricular cardiomyopathy, myofibrillar myopathy 1, dilated cardiomyopathy 1I, neurogenic scapuloperoneal syndrome, Kaeser type, familial isolated dilated cardiomyopathy, dilated cardiomyopathy.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001927.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DES	NM_001927.4	MANE Select	c.1360C>T	p.Arg454Trp	missense	Exon 8 of 9	NP_001918.3
	DES	NM_001382708.1		c.1357C>T	p.Arg453Trp	missense	Exon 8 of 9	NP_001369637.1
	DES	NM_001382712.1		c.1360C>T	p.Arg454Trp	missense	Exon 8 of 9	NP_001369641.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DES	ENST00000373960.4	TSL:1 MANE Select	c.1360C>T	p.Arg454Trp	missense	Exon 8 of 9	ENSP00000363071.3	P17661
	DES	ENST00000942906.1		c.1483C>T	p.Arg495Trp	missense	Exon 9 of 10	ENSP00000612965.1
	DES	ENST00000942898.1		c.1474C>T	p.Arg492Trp	missense	Exon 8 of 9	ENSP00000612957.1

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Desmin-related myofibrillar myopathy (4)
4	-	-	not provided (5)
2	-	-	Cardiovascular phenotype (2)
1	-	-	Desmin-related myofibrillar myopathy;C1858154:Dilated cardiomyopathy 1I;C1867005:Neurogenic scapuloperoneal syndrome, Kaeser type (1)
1	-	-	Primary dilated cardiomyopathy (1)
1	-	-	Primary dilated cardiomyopathy;C0027868:Neuromuscular disease (1)
1	-	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

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
Polyphen		1.0	D
Vest4		0.66
MVP		0.99
MPC		1.4
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;