rs727504448

chr2-219420115-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001927.4(DES):c.600del(p.Lys201ArgfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L200L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DES NM_001927.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.53

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 11 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 2-219420115-TG-T is Pathogenic according to our data. Variant chr2-219420115-TG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178660.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=1, Uncertain_significance=1}. Variant chr2-219420115-TG-T is described in Lovd as [Pathogenic]. Variant chr2-219420115-TG-T is described in Lovd as [Pathogenic]. Variant chr2-219420115-TG-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DES	NM_001927.4	c.600del	p.Lys201ArgfsTer20	frameshift_variant	2/9	ENST00000373960.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DES	ENST00000373960.4	c.600del	p.Lys201ArgfsTer20	frameshift_variant	2/9	1	NM_001927.4	P1
DES	ENST00000477226.6	n.74del		non_coding_transcript_exon_variant	1/8	4
DES	ENST00000492726.1			upstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461892 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Desmin-related myofibrillar myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 27, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 178660). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive DES-related conditions (PMID: 23815709). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys201Argfs*20) 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 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 05, 2012

The Lys201fs variant in DES has not been previously reported in the literature b ut has been identified by our laboratory in 1 family, where it was present in tr ans with a second DES variant (nonsense) in 2 individuals with features consiste nt with a desminopathy. Each unaffected parent carried 1 of the variants, sugge stive of recessive inheritance. This frameshift variant is predicted to alter th e protein?s amino acid sequence beginning at position 201 and lead to a prematur e termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. The spectrum of reported DES variants includes several similar variants (nonsense, splice, frameshift; Park 2000, Sch roeder 2003, Dunand 2009, Hong 2011, Wahbi 2011). One of these variants (Dunand 2009) showed clear autosomal dominant inheritance but this could not be conclus ively established for other variants. In summary, this variant is likely to be p athogenic though studies in 1 family suggest that it may not result in disease w hen present in isolation. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 20, 2023

The c.600delG variant, located in coding exon 2 of the DES gene, results from a deletion of one nucleotide at nucleotide position 600, causing a translational frameshift with a predicted alternate stop codon (p.K201Rfs*20). This alteration has been detected in trans with another truncating DES variant in siblings with profound, childhood-onset skeletal myopathy, respiratory dysfunction, and dilated cardiomyopathy (McLaughlin HM et al. BMC Med Genet, 2013 Jul;14:68). Although biallelic loss of function alterations in DES have been associated with autosomal recessive DES-related myofibrillar myopathy, haploinsufficiency for DES has not been clearly established as a mechanism of disease for autosomal dominant DES-related myopathy. Based on the supporting evidence, this variant is expected to be causative of autosomal recessive DES-related myofibrillar myopathy when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant DES-related myopathy is unclear. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs727504448; hg19: chr2-220284837;