Submissions for variant NM_004415.4(DSP):c.5680_5683del (p.Ser1894fs)

dbSNP: rs774763657

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000458285	SCV000543241	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1894Leufs*34) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 978 amino acid(s) of the DSP protein. This variant is present in population databases (rs774763657, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with DSP-related conditions. ClinVar contains an entry for this variant (Variation ID: 405232). This variant disrupts a region of the DSP protein in which other variant(s) (p.Thr2634Lysfs*4) have been determined to be pathogenic (PMID: 11063735). 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.
GeneDx	RCV000522863	SCV000618362	likely pathogenic	not provided	2023-05-16	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Reported as part of a multi-database review of ARVC-related variants; no clinical information was provided (PMID: 31402444); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11063735, 31402444)
Color Diagnostics, LLC DBA Color Health	RCV001525149	SCV001735191	likely pathogenic	Cardiomyopathy	2023-11-16	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 24 of the DSP gene, creating a frameshift and premature translation stop signal in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing an altered C-terminal sequence. Although functional studies have not been reported, this variant is expected to disrupt the plakin repeat domains and downstream C-terminal sequence, which 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 (for example, ClinVar variation ID: 199903, 222582). To our knowledge, this variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/251232 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics	RCV002348274	SCV002647831	pathogenic	Cardiovascular phenotype	2020-04-14	criteria provided, single submitter	clinical testing	The c.5680_5683delAGTC pathogenic mutation, located in coding exon 24 of the DSP gene, results from a deletion of 4 nucleotides at nucleotide positions 5680 to 5683, causing a translational frameshift with a predicted alternate stop codon (p.S1894Lfs*34). Alterations in DSP that result in haploinsufficiency or protein truncation have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM) (Fressart V et al. Europace. 2010;12(6):861-8; Elliott P et al. Circ Cardiovasc Genet. 2010;3(4):314-22; Quarta G et al. Circulation. 2011;123(23):2701-9; Garcia-Pavia P et al. Heart. 2011;97(21):1744-52; Rasmussen TB et al. Clin Genet. 2013;84(1):20-30; Pugh TJ et al. Genet Med. 2014;16(8):601-8). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000522863	SCV003799889	likely pathogenic	not provided	2022-05-04	criteria provided, single submitter	clinical testing	The DSP c.5680_5683delAGTC; p.Ser1894LeufsTer34 variant (rs774763657) is reported in the literature in an individual diagnosed with arrhythmogenic right ventricular cardiomyopathy (Ye 2019) and is reported as pathogenic/likely pathogenic in ClinVar (Variation ID: 405232). This variant is found on only three chromosomes in the Genome Aggregation Database (3/251,232 alleles), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the DSP gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein missing the last 978 amino acids of the normal DSP protein. Truncating variants downstream of c.5680_5683delAGTC are reported in patients with cardiomyopathy and are considered disease-causing (Castelletti 2017, Fressart 2010). Based on available information, the c.5680_5683delAGTC variant is considered to be likely pathogenic. References: Castelletti S et al. Desmoplakin missense and non-missense mutations in arrhythmogenic right ventricular cardiomyopathy: Genotype-phenotype correlation. Int J Cardiol. 2017 Dec 15;249:268-273. Fressart V et al. Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice. Europace. 2010 Jun;12(6):861-8. Ye JZ et al. Reevaluation of genetic variants previously associated with arrhythmogenic right ventricular cardiomyopathy integrating population-based cohorts and proteomics data. Clin Genet. 2019 Dec;96(6):506-514.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330690	SCV004038767	pathogenic	Familial isolated arrhythmogenic right ventricular dysplasia	2023-08-21	criteria provided, single submitter	clinical testing	Variant summary: DSP c.5680_5683delAGTC (p.Ser1894LeufsX34) results in a premature termination codon and is predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. Although the variant is not predicted to cause absence of the protein through nonsense mediated decay, the variant is predicted to disrupt the last 978 amino acids in the protein sequence. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251232 control chromosomes (gnomAD). To our knowledge, no occurrence of c.5680_5683delAGTC in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters have assessed the variant since 2014: three classified the variant as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001525149	SCV004240537	uncertain significance	Cardiomyopathy	2022-07-18	criteria provided, single submitter	clinical testing