rs747289875

chr2-219418830-TC-T

Variant summary

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

The NM_001927.4(DES):c.369del(p.Ile123MetfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,430,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: DES NM_001927.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.937

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 2-219418830-TC-T is Pathogenic according to our data. Variant chr2-219418830-TC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228548.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DES	NM_001927.4	c.369del	p.Ile123MetfsTer18	frameshift_variant	1/9	ENST00000373960.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DES	ENST00000373960.4	c.369del	p.Ile123MetfsTer18	frameshift_variant	1/9	1	NM_001927.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000100 AC: 2 AN: 199734 Hom.: 0 AF XY: 0.0000187 AC XY: 2 AN XY: 107128

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 SAS exome AF: 0.0000776

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000280 AC: 4 AN: 1430162 Hom.: 0 Cov.: 92 AF XY: 0.00000424 AC XY: 3 AN XY: 708280

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: 0.0000488

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 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 24, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 228548). This variant has not been reported in the literature in individuals affected with DES-related conditions. This variant is present in population databases (rs747289875, gnomAD 0.008%). This sequence change creates a premature translational stop signal (p.Ile123Metfs*18) 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). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 20, 2015

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ile123fs variant in DES has not been previously reported in individuals with cardiomyopat hy, but has been identified in at least 2 South Asian chromosomes by the Exome A ggregation Consortium. However, data from large population studies is insufficie nt to assess the frequency of this variant (ExAC, http://exac.broadinstitute.org ). This variant is predicted to cause a frameshift, which alters the protein?s a mino acid sequence beginning at position 123 and leads to a premature terminatio n codon 18 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Truncating DES variants have been reported in a n umber of individuals with a range of phenotypes including myopathy, DCM, HCM, an d/or conduction system disease (Park 2000, Dalakas 2000, Schroder 2003, Dunand 2 009, Hong 2010, Wahbi 2012, McLaughlin 2013) and both dominant and recessive mod es of inheritance have been described (Dunand 2009, Wahbi 2012, McLaughlin 2013) . However, the effect of truncating variants in the DES gene has not been fully elucidated. In summary, while there is some suspicion for a pathogenic role, th e clinical significance of the p.Ile123fs variant is uncertain. -

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: rs747289875; hg19: chr2-220283552;