Variant rs727504448 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

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 Likely pathogenic (★★). 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

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2U:1

Conservation

PhyloP100: 1.53

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 2-219420115-TG-T is Pathogenic according to our data. Variant chr2-219420115-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 178660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. 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	Protein	UniProt
DES	NM_001927.4 linkuse as main transcript	c.600del	p.Lys201ArgfsTer20	frameshift_variant	2/9	ENST00000373960.4	NP_001918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DES	ENST00000373960.4 linkuse as main transcript	c.600del	p.Lys201ArgfsTer20	frameshift_variant	2/9	1	NM_001927.4	ENSP00000363071	P1
DES	ENST00000477226.6 linkuse as main transcript	n.74del		non_coding_transcript_exon_variant	1/8	4
DES	ENST00000492726.1 linkuse as main transcript			upstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

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:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

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:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Desmin-related myofibrillar myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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, flagged submission

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

Name

Calibrated prediction

Score

Prediction

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

Other links and lift over