Submissions for variant NM_004415.4(DSP):c.242G>A (p.Cys81Tyr)

gnomAD frequency: 0.00014  dbSNP: rs140965835

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038009	SCV000061675	uncertain significance	not specified	2018-04-10	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000766871	SCV000233557	likely benign	not provided	2023-04-25	criteria provided, single submitter	clinical testing	Reported in a individual with arrhythmogenic right ventricular cardiomyopathy (ARVC); however, this individual also harbored a canonical splice site variant in the PKP2 gene, which was identified in an affected sibling who did not harbor the p.(C81Y) variant (Christensen et al., 2010); Reported in additional unrelated individuals with idiopathic ventricular fibrillation, conduction disease, left ventricular noncompaction cardiomyopathy (LVNC) and/or left ventricular hypertrabeculation, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and ARVC (Visser et al., 2017; Arbustini et al., 2017; Miszalski-Jamka et al., 2017; van Lint et al., 2019; Marschall et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28798025, 28254189, 31737537, 30847666, 20864495, 28087426)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470962	SCV000543280	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2025-01-30	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000590870	SCV000700091	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770229	SCV000901660	uncertain significance	Cardiomyopathy	2017-04-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770229	SCV000914072	uncertain significance	Cardiomyopathy	2024-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 81 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy, who also carried a pathogenic variant in the PKP2 gene that could explain the observed phenotype (PMID 20864495). This variant has been reported in individuals affected with idiopathic ventricular fibrillation (PMID: 28087426), conduction disease (PMID: 28254189) and left ventricular noncompaction (PMID: 28798025). This variant has been identified in 45/282656 chromosomes (37/128999 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV001159441	SCV001321157	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2018-03-08	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001159442	SCV001321158	uncertain significance	Woolly hair-skin fragility syndrome	2018-03-08	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001160814	SCV001322643	uncertain significance	Lethal acantholytic epidermolysis bullosa	2018-03-08	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038009	SCV002500169	uncertain significance	not specified	2023-12-11	criteria provided, single submitter	clinical testing	Variant summary: DSP c.242G>A (p.Cys81Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 1614108 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (0.00014 vs 0.0002), allowing no conclusion about variant significance. c.242G>A has been reported in the literature as a VUS in settings of multigene panel testing among individuals affected with a variety of phenotypes such as ARVC, idiopathic ventricular fibrillation (IVF), left ventricular hypertrabeculation (LVHT) or LVNC, conduction disease, referral cohort for genetic testing based on a suspected diagnosis of LQTS, BrS, CPVT, HCM, DCM or ARVC (example, Christensen_2010, Visser_2017, Miszalski-Jamka_2017, Arbustini_2017, Marschall_2019). At-least one individual diagnosed with ARVC carried a causative variant in the PKP2 gene that co-segregated with disease in the family, whereas this variant did not (example, Christensen_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS=7, likely benign =3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000766871	SCV002542154	uncertain significance	not provided	2021-10-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453313	SCV002737511	likely benign	Cardiovascular phenotype	2021-06-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002490516	SCV002799599	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Lethal acantholytic epidermolysis bullosa; Woolly hair-skin fragility syndrome; Keratosis palmoplantaris striata 2; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis	2022-03-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996336	SCV004822026	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 81 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy, who also carried a pathogenic variant in the PKP2 gene that could explain the observed phenotype (PMID 20864495). This variant has been reported in individuals affected with idiopathic ventricular fibrillation (PMID: 28087426), conduction disease (PMID: 28254189) and left ventricular noncompaction (PMID: 28798025). This variant has been identified in 45/282656 chromosomes (37/128999 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001159441	SCV005399532	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ARVC (MIM#607450) and other DSP-related cardiac disorders. (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. Age-dependent penetrance and variable expressivity are well-described aspects of arrhythmogenic cardiomyopathy (PMID: 29062697). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (45 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated region which interacts with plakophilin 1 and junction plakoglobin (UniProt). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Cys81Phe) variant has a VUS entry in ClinVar. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as a VUS in individuals with idiopathic ventricular fibrillation, HCM, DCM, LVNC, and left ventricular hypertrabeculation (PMID: 28087426, PMID: 30847666, PMID: 28798025, ClinVar). This variant has been identified in an individual with ARVC who had an additional PKP2 canonical splice variant (PMID: 20864495). This variant has also been identified in control individuals (PMID: 20864495) and has conflicting interpretations of pathogenicity in the LOVD database. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 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