2-219423787-C-T

Variant names:

• chr2-219423787-C-T
• rs62635763
• NM_001927.4:c.1255C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001927.4(DES):​c.1255C>T​(p.Pro419Ser) variant causes a missense change. 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. P419L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DES NM_001927.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 6.65
• Publications: 16 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

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-219423788-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287812.
• 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, 0.955
• PP5: Variant 2-219423787-C-T is Pathogenic according to our data. Variant chr2-219423787-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39718.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DES	NM_001927.4	MANE Select	c.1255C>T	p.Pro419Ser	missense	Exon 7 of 9	NP_001918.3
	DES	NM_001382708.1		c.1252C>T	p.Pro418Ser	missense	Exon 7 of 9	NP_001369637.1
	DES	NM_001382712.1		c.1255C>T	p.Pro419Ser	missense	Exon 7 of 9	NP_001369641.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DES	ENST00000373960.4	TSL:1 MANE Select	c.1255C>T	p.Pro419Ser	missense	Exon 7 of 9	ENSP00000363071.3
	DES	ENST00000477226.6	TSL:4	n.729C>T		non_coding_transcript_exon	Exon 6 of 8
	DES	ENST00000492726.1	TSL:4	n.650C>T		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Desmin-related myofibrillar myopathy Pathogenic:4

Dec 12, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with serine at codon 419 of the DES protein (p.Pro419Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with autosomal dominant desminopathies in several families (PMID:17418574, 22153487, 22395865, 26431784). ClinVar contains an entry for this variant (Variation ID: 39718). Experimental studies have shown that this missense change forms filaments and does not induce aggregation in cell lines (PMID: 23032110). For these reasons, this variant has been classified as Pathogenic.

Sep 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.P419S in DES (NM_001927.4) has been previously reported in multiple patients with autosomal dominant desminopathies (Olivé M et al,Wahbi K et al). Functional studies reveal a damaging effect (Brodehl A et al). The variant has been submitted to ClinVar as Pathogenic.The p.P419S variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between proline and serine. The p.P419S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 419 of DES is conserved in all mammalian species. The nucleotide c.1255 in DES is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

Feb 11, 2019

Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

not provided Pathogenic:1 Other:1

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Mar 07, 2016

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Pathogenic:1

May 17, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P419S variant (also known as c.1255C>T), located in coding exon 7 of the DES gene, results from a C to T substitution at nucleotide position 1255. The proline at codon 419 is replaced by serine, an amino acid with similar properties. This variant was identified in one or more individuals with features consistent with DES-related myopathy (Olivé M et al. Neuromuscul Disord, 2007 Jun;17:443-50; Hedberg C et al. Eur J Hum Genet, 2012 Sep;20:984-5; Wahbi K et al. Neuromuscul Disord, 2012 Mar;22:211-8; Maerkens A et al. J Proteomics, 2013 Sep;90:14-27; Ripoll-Vera T et al. Rev Esp Cardiol (Engl Ed), 2015 Nov;68:1027-9; Silva AMS et al. J Neuropathol Exp Neurol, 2022 Aug;81:746-757; Wang Q et al. J Neuromuscul Dis, 2024 Nov;11:1247-1259) and segregated with disease in at least one family (Olivé M et al. Neuromuscul Disord, 2007 Jun;17:443-50; Hedberg C et al. Eur J Hum Genet, 2013 Jun;21:590; Ripoll-Vera T et al. Rev Esp Cardiol (Engl Ed), 2015 Nov;68:1027-9). In an assay testing DES function, this variant showed a functionally abnormal result (Brodehl A et al. Eur J Hum Genet, 2013 Jun;21:589-90). 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 majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
CardioboostCm	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.073	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		6.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.72
Sift	Benign	0.074	T
Sift4G	Benign	0.069	T
Polyphen		0.77	P
Vest4		0.92
MutPred		0.82		Loss of catalytic residue at N417 (P = 0.1002)
MVP		0.95
MPC		0.88
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.32
gMVP		0.82
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs62635763; hg19: chr2-220288509; COSMIC: COSV100900438; COSMIC: COSV100900438;