DSC2

Gene Facts

• HGNC Symbol: DSC2 (HGNC:3036)
• HGNC Name: desmocollin 2
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: DSC3
• Alias symbols: CDHF2
• %HI: 70.44
• pLI: 0
• LOEUF: 0.74
• Cytoband: 18q12.1
• Genomic Coordinates:

  GRCh37/hg19:	chr18:28638806-28682384
  GRCh38/hg38:	chr18:31058840-31102421

• MANE Select Transcript: NM_024422.6 ENST00000280904.11
• Function: Component of intercellular desmosome junctions. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion. May contribute to epidermal cell positioning (stratification) by mediating differential adhesiveness between cells that express different isoforms. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-13511
• ClinGen Curation ID: CCID:007033
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Little Evidence for Haploinsufficiency (1)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 04/24/2024

Haploinsufficiency (HI) Score Details

• HI Score: 1
• HI Evidence Strength: Little Evidence for Haploinsufficiency

HI Disease

• arrhythmogenic right ventricular dysplasia 11

HI Evidence

• PUBMED: 17186466
  Heuser et al. (2006), describe a patient with arrhythmogenic right ventricular dysplasia/cardiomyopathy (AVRD/C). This patient was found to be a heterozygous carrier of a novel splice-site mutation in intron 5 (c.631-2ArG) of DSC2, which is predicted to lead to the production of a premature stop codon. Quantification of DSC2 expression in heart tissue demonstrated that the patient had a significant decrease in the mutant DSC2 transcript, with approximately 50% of the normal transcript remaining, while western blot analysis showed a decrease in the total DSC2 protein level. Based on these results the authors suggest that nonsense-mediated mRNA decay and haploinsufficiency are likely contributing to the disease mechanism in this patient. This variant has also been observed in clinical and research laboratories and reported in ClinVar; as of the time of this review, classifications were conflicting. One clinical laboratory, Laboratory for Molecular Medicine, states the following in their evaluation: "[this variant] reported in a 110-year-old individual (Gierman 2014) and in ClinVar (Variation ID: 16850). This variant has been identified in 4/111556 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence, and in vitro studies confirmed that it leads to aberrant splicing and reduced DSC2 protein levels (Heuser 2006). Splice and other loss-of-function variants in DSC2 have been reported in individuals with ARVC; however, the clinical significance of these variants is not yet fully understood. Although ARVC has primarily been described as a dominant disorder, in several reports of loss-of function variants, only those individuals with a variant on the second allele were affected, suggesting that LOF variants may either act in a recessive manner or have a much milder effect than missense variants. In summary, while there is some suspicion for a pathogenic role in the heterozygous state, the clinical significance of the c.631-2A>G variant, with regard to dominant ARVC is uncertain."
• PUBMED: 17033975
  Syrris et al. (2006) describe four probands with variants in DSC2 presenting with AVRD/C. In Family A, a single nucleotide deletion in exon 10 resulting in a frameshift mutation (M477fsX480) in the proband and her mother was predicted to result in premature termination. In families B, C, and D, the probands had a 2 bp insertion in exon 17 ((2687_2688insGA), also predicted to result in premature termination because of frameshift. Families B, C, and D all had a positive family history of sudden cardiac death, although there appears to be incomplete penetrance in mutation carriers. The authors speculate that the deletion mutation in Family A results in haploinsufficiency; however there are no functional studies that support this association. The functional result of the 2 bp insertion in the other families is more difficult to determine without functional studies, since DSC2 produces two transcripts due to alternative splicing in exon 16. This variant has been observed by several clinical laboratories and reported in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/46186/) as Benign/Likely Benign; it is also observed at a high allele frequency in gnomad v4.1. For these reasons, these cases are not being considered as evidence toward haploinsufficiency.
• PUBMED: 29178656
  Wada et al. (2017) describe genotyping of 99 unrelated Japanese ARVD/C probands for risk genes(PKP2, DSG2, DSP, DSC2) to see the characteristics of probands with pathogenic variants of these genes. The description of the cohort is very limited to genotype information with a novel mutation of c.296_297 insA causing frameshift, p.Ser99fs.
• PUBMED: 31386562
  Van-Lint et al. (2019), describe 501 ARVD probands associated with variants of the desmosomal genes(PKP2, DSP, DSG2, and JUP) based on 3 ARVD registries in US and Europe. The purpose of the study was to investigate whether they are de novo vs. nonunique from ancient founders. He quoted 'Most(desmosomal genes) were splice-site or truncating variants.' The description of the cohort is very limited to genotype information. 4 variants were described; c.154+1G>A(no p. information), c.882dupA (p.Phe295Ilefs), c.943-1G>A(no p. information), c.2582_2585dup (p.Gly863Lysfs*13) (note: NMD is not expected for this variant).
• PUBMED: 33684294
  Carruth et al. (2021), describe genome sequencing results of presymptomatic (no existing ARVD Dx; individuals participating in a biobank) cohorts for desmosome Genes(DSP, DSC2, PKP2) in an effort to screen for ARVD: All reported variants were putatively truncating(null);50%(2/4) of DSC2 variants were met with minor criteria(arrhythmia and/or repolarization) only. The article listed 8 variants as follows: c.123delC(p.Lys42AsnfsX2), c.663T>A (p.Tyr221X), c.880delC (p.Leu294TyrfsX10),c.1167G>A (p.Trp389X), c.2200C>T (p.Gln734X), c.2250+1G>C (p.?), c.2431G>T (p.Gly811X), and c.2463C>A (p.Tyr821X). Two of these individuals were found to have minor criteria for ARVD/C upon clinical investigation; the authors did not specify which of the 8 variants these individuals had.

• HI Evidence Comments: Although several publications with loss-of-function-type variants have been reported, due to the variable inheritance patterns, mutational spectrum, and lack of reports of whole gene deletions, the haploinsufficiency score is 1. For a discussion of the estimated penetrance of putative loss of function variants in ARVD/C-associated genes (including but not limited to DSC2), please see Carruth et al. (2019) (https://pubmed.ncbi.nlm.nih.gov/31638835/). DSC2 encodes the desmosomal cadherin, desmocollin 2. Sequence-level variants in DSC2 are associated with arrhythmogenic right ventricular cardiomyopathy 11 (AVRC) (OMIM: 610476), a genetically heterogeneous cardiovascular disorder characterized by fibrofatty replacement of the right ventricular myocardium, ventricular arrhythmia, and an increased risk of premature sudden cardiac death. A large number (n>50) of DSC2 variants have been reported in the literature, the majority of which are missense mutations. Several mutations that may confer a loss-of-function have also been reported, including splice-site, intragenic deletions/duplications, and nonsense mutations, which have been observed in association with both autosomal dominant (PMID: 17186466 and 17033975) and autosomal recessive (PMID: 20400443, 19863551, 24793512, 23863954) forms of AVRC. Incomplete penetrance for some DSC2 variants has also been observed. Of note: Gehmlich et al. (2010) used transient transfection assays to study the function and expression of missense and frameshift mutations in DSC2. The authors conclude that the missense mutations result in a decrease of available DCS2 mature functional protein, and this decrease, rather than a dominant negative effect, is responsible for features of AVRD/C. The functional studies on the frameshift mutation did not show a decrease in the amount of mature functional protein, but did show a decreased affinity to its binding partner plakoglobin (PG). The authors note that in vivo studies are still required to accurately assess the functional effects of mutations (PMID: 21062920).

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: At this time there is no evidence that supports the triplosensitivity of this gene.