ClinVar Genomic variation as it relates to human health

Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32880476)

The frame shift (c.7773_7776del) variant has been reported previously in patients affected with Cardiomyopathy, dilated, with woolly hair and keratoderma (Verdonschot et. al. , 2020). This variant disrupts a region of the DSP protein in which other variant(s) (p.Glu2728Glyfs*11) have been determined to be pathogenic. The p.Ser2591ArgfsTer11 variant is novel (not in any individuals) in 1000 Genomes and has an allele frequency of 0.001% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic and Variant of Uncertain Significance (VUS). This variant causes a frameshift starting with codon Serine 2591, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 11 of the new reading frame, denoted p.Ser2591ArgfsTer11. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. The observed variant lies in the last exon. For these reasons, this variant has been classified as Pathogenic.

This variant causes a deletion of 4 nucleotides in exon 24 of the DSP gene, creating a frameshift and premature translation stop signal in the last exon. Although functional studies have not been reported, this variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein with disruption to the linker region between the C-terminal plakin repeat domains B and C and downstream C-terminal sequence that have been reported to be essential for interaction with intermediate filaments (PMID: 12101406, 12802069, 21756917). In addition, truncating variants occurring downstream of this variant are known to be disease-causing (ClinVar variation ID: 246676, 263803). This variant has been reported in a few individuals affected with dilated cardiomyopathy (PMID: 32880476, Burns 2019, dissertation, The University of Sydney). This variant has been identified in 3/251484 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

This sequence change creates a premature translational stop signal (p.Ser2591Argfs*11) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 281 amino acid(s) of the DSP protein. This variant is present in population databases (rs763560697, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 32880476). ClinVar contains an entry for this variant (Variation ID: 923199). This variant disrupts a region of the DSP protein in which other variant(s) (p.Glu2728Glyfs*11) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

This variant causes a deletion of 4 nucleotides in exon 24 of the DSP gene, creating a frameshift and premature translation stop signal in the last exon. Although functional studies have not been reported, this variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein with disruption to the linker region between the C-terminal plakin repeat domains B and C and downstream C-terminal sequence that have been reported to be essential for interaction with intermediate filaments (PMID: 12101406, 12802069, 21756917). In addition, truncating variants occurring downstream of this variant are known to be disease-causing (ClinVar variation ID: 246676, 263803). This variant has been reported in a few individuals affected with dilated cardiomyopathy (PMID: 32880476, Burns 2019, dissertation, The University of Sydney). This variant has been identified in 3/251484 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.