Submissions for variant NM_004415.4(DSP):c.6310del (p.Thr2104fs)

gnomAD frequency: 0.00003  dbSNP: rs730880092

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000157216	SCV000206940	likely pathogenic	Cardiomyopathy	2015-01-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000157216	SCV001734693	likely pathogenic	Cardiomyopathy	2020-12-16	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 24 of the DSP gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to result in the expression of a truncated protein product lacking C-terminal plakin repeat domains that bind intermediate filaments. This variant has been reported in heterozygous state in ten unrelated Finnish individuals (PMID: 26084686, 32005173), including nine individuals affected with dilated cardiomyopathy and one affected individual with slightly dilated ventricles. Subsequently, seven additional family members have been identified to carry this variant. Four of these individuals were affected with dilated cardiomyopathy or other cardiac abnormalities, and three individuals were unaffected. Furthermore, most of the carriers with dilated cardiomyopathy showed an arrhythmogenic phenotype (PMID: 32005173). This variant has also been reported in the compound heterozygous state with another truncation or missense variant in two individuals affected with severe cardiomyopathies and skin, hair, and/or tooth abnormalities (PMID: 19924139, 24341478). Desmoplakin was either not expressed or reduced in skin biopsies from the two individuals. Heterozygous family members were unaffected in both families. This variant has been identified in 13/251432 chromosomes (11/21648 Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Multiple truncations variants that lie downstream of this variant are known to cause arrhythmogenic right ventricular cardiomyopathy and dilated cardiomyopathy (ClinVar). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003764988	SCV004569798	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-02-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr2104Glnfs*12) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 768 amino acid(s) of the DSP protein. This variant is present in population databases (rs730880092, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with clinical features of DSP-related conditions (PMID: 19924139, 24341478, 35653365). ClinVar contains an entry for this variant (Variation ID: 180343). 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.
GeneDx	RCV004700486	SCV005201567	pathogenic	not provided	2023-06-27	criteria provided, single submitter	clinical testing	Observed with a second DSP variant in trans in individuals with cardiomyopathy, skin and hair phenotypes, and immunohistochemistry on a skin biopsy consistent with loss of desmoplakin expression (PMID: 24341478, 19924139); Segregates with disease in many affected individuals from several families with DCM and/or other DSP-related features in published literature, and is suggested to be a founder variant in the Finnish population (PMID: 37008330, 32005173); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34400560, 35445468, 36142674, 29633331, 19924139, 33132336, 34343150, 35653365, 26084686, 36580316, 32005173, 37008330, 24341478)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786418	SCV005398126	pathogenic	Arrhythmogenic right ventricular dysplasia 8	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with arrhythmogenic right ventricular dysplasia 8 (MIM#607450) and other DSP-related cardiac disorders (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants in this gene are usually inherited in a dominant manner, however rare reports of recessive inheritance have resulted in a more severe cardiac phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 29062697). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a condition (13 heterozygotes, 0 homozygotes). (SP) 0601 - Variant results in the loss of the well-established functional C-terminal EGFP, PRD2/B and PRD3/C domains (PMID: 30354334). (SP) 0701 - Other protein truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported as pathogenic, and observed in individuals with arrhythmogenic right ventricular dysplasia (ARVC) and dilated cardiomyopathy (DCM) (Decipher, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been described as likely pathogenic (ClinVar) and as a founder variant within the Finnish population. It has been observed in multiple heterozygous individuals with DCM, arrhythmogenic cardiomyopathy and sudden cardiac death (PMID: 32005173). It has also been found in two compound heterozygous children with DCM, woolly hair and keratoderma (PMID: 19924139, PMID: 24341478). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV003234551	SCV003931137	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-06-12	no assertion criteria provided	literature only