rs150974575

chr2-219423817-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001927.4(DES):c.1285C>T(p.Arg429Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DES NM_001927.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.08

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-219423817-C-T is Pathogenic according to our data. Variant chr2-219423817-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219423817-C-T is described in Lovd as [Pathogenic]. Variant chr2-219423817-C-T is described in Lovd as [Pathogenic]. Variant chr2-219423817-C-T is described in Lovd as [Pathogenic]. Variant chr2-219423817-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DES	NM_001927.4	c.1285C>T	p.Arg429Ter	stop_gained	7/9	ENST00000373960.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DES	ENST00000373960.4	c.1285C>T	p.Arg429Ter	stop_gained	7/9	1	NM_001927.4	P1
DES	ENST00000477226.6	n.759C>T		non_coding_transcript_exon_variant	6/8	4
DES	ENST00000492726.1	n.680C>T		non_coding_transcript_exon_variant	6/6	4
DES	ENST00000683013.1	n.673C>T		non_coding_transcript_exon_variant	5/7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251480 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461642 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000120 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33874732, 24503780, 31402444, 27532257, 25590979, 23815709) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 04, 2016	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Desmin-related myofibrillar myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 01, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 177872). This premature translational stop signal has been observed in individual(s) with autosomal recessive DES-related conditions (PMID: 23815709, 25590979). This variant is present in population databases (rs150974575, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg429*) in the DES gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DES are known to be pathogenic (PMID: 23575897). -

Primary dilated cardiomyopathy;C0027868:Neuromuscular disease;C1832370:Desmin-related myofibrillar myopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 12, 2013

The Arg429X variant in DES has not been previously reported in individuals with isolated cardiomyopathy, but has been identified in 1/8600 European American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS/; dbSNP rs150974575). It has also been identified by ou r laboratory in 1 family, where it was present in trans with a second DES varian t (frameshift) in 2 individuals with features consistent with a desminopathy. Ea ch unaffected parent carried 1 of the variants, which is suggestive of recessive inheritance. This variant leads to a premature termination codon at position 42 9, which is predicted to lead to a truncated or absent protein. The spectrum of reported DES variants includes several similar variants (nonsense, splice, frame shift; Park 2000, Schroeder 2003, Dunand 2009, Hong 2011, Wahbi 2011). While one of these variants (Dunand 2009) showed clear autosomal dominant inheritance, th is could not be conclusively established for the other variants. In summary, thi s variant is likely to cause disease when present with a second DES variant, but additional studies are needed to fully establish its clinical significance. -

Primary familial dilated cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 21, 2022

Variant summary: DES c.1285C>T (p.Arg429X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. Truncations downstream of this position have been reported in association with cardiomyopathy in HGMD. The variant allele was found at a frequency of 1.2e-05 in 251480 control chromosomes. c.1285C>T has been reported in the literature in individuals affected with skeletal myopathy and cardiomyopathy, in addition to other features, in two unrelated individuals who also carried second truncating DES mutations, and in both cases the individuals had a family history of the phenotype (McLaughlin_2013, Zhu_2015). While DES variants are most commonly autosomal dominant or de novo dominant missense mutations, a few rare cases of autosomal recessive desminopathy have been described ranging from severe infantile to adult-onset, with variable phenotypic presentations affecting skeletal, cardiac and smooth muscle. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A
Vest4		0.95
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150974575; hg19: chr2-220288539;