Submissions for variant NM_004415.4(DSP):c.943C>T (p.Arg315Cys)

gnomAD frequency: 0.00016  dbSNP: rs200476515

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038121	SCV000061787	uncertain significance	not specified	2019-06-21	criteria provided, single submitter	clinical testing	The p.Arg315Cys variant in DSP (ClinVar variation ID #24440) has been reported in 4 individuals with ARVC, two of whom carried an additional variant sufficient to explain their phenotype (1 in DSP and 1 in PKP2), and in 1 individual with left ventricular dilation (Bhonsale 2015, Ermakov 2014, Walsh 2017, LMM data). This variant was also identified in 3 individuals with childhood onset DCM from two families (LMM data). Two of these (from one family) also carried a pathogenic DSP loss of function variant and had a more severe course of disease than other family members who had only the loss of function variant, suggesting that the p.Arg315Cys variant may have added to disease severity. In addition, this variant has been reported in 2 individuals with Brugada syndrome, one of whom also carried a pathogenic variant in SCN5A (Zhang 2016, Zhao 2016). This variant has been identified in 0.08% (16/19928) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is higher than the maximum expected allele frequency for a pathogenic variant causing autosomal dominant ARVC although it remains compatible with autosomal recessive inheritance, which has been described for DSP. Computational prediction tools and conservation analysis suggest that the Arg315Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the Arg315Cys variant is uncertain. ACMG/AMP Criteria applied: PP3, PM3, BS1_Supporting.
GeneDx	RCV000766874	SCV000233573	likely benign	not provided	2020-09-10	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26585738, 25196244, 25616645, 27532257, 27707468, no PMID, 25820315, 24503780, 30847666, 32516855)
Invitae	RCV000232142	SCV000288555	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000322105	SCV000464870	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000355871	SCV000464871	uncertain significance	Woolly hair-skin fragility syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000263737	SCV000464872	uncertain significance	Lethal acantholytic epidermolysis bullosa	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV000620186	SCV000738209	uncertain significance	Cardiovascular phenotype	2022-05-25	criteria provided, single submitter	clinical testing	The p.R315C variant (also known as c.943C>T), located in coding exon 8 of the DSP gene, results from a C to T substitution at nucleotide position 943. The arginine at codon 315 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomyopathy, and Brugada syndrome cohorts, but many of the individuals had variants in other cardiac-related genes (Ermakov S et al. Pacing Clin Electrophysiol. 2014;37:1708-16; Pugh TJ et al. Genet. Med. 2014;16:601-8; Bhonsale A et al. Eur. Heart J. 2015;36:847-55; Zhang L et al. Mayo Clin. Proc. 2016;91:1503-1514; Walsh R et al. Genet. Med. 2017;19:192-203). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for an autosomal dominant disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). However, one functional study indicated that mice homozygous for p.R315C display phenotypes associated with ARVC in humans, suggesting the possibility that this variant may be pathogenic in the autosomal recessive state (Liang Y et al. J Clin Invest, 2021 06;131(11):e137689). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770231	SCV000901662	uncertain significance	Cardiomyopathy	2017-07-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770231	SCV000913726	uncertain significance	Cardiomyopathy	2023-01-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 315 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant disrupts the DSP and CSN6 interaction in vitro and cardiomyocyte-specific DSP knockout mice exhibit baseline electrical defects associated with arrhythmogenic right ventricular cardiomyopathy as well as a significant increase in catecholamine induced arrhythmias when compared with wild-type controls (PMID: 33857019 ). This variant has been reported in individuals affected with arrhythmogenic cardiomyopathy, dilated cardiomyopathy, and Brugada syndrome (PMID: 24503780, 25196244, 25616645, 26585738, 27532257, 31983221, 32516855). Three of these individuals also carried pathogenic variants in different genes suggesting that this variant may not have been the cause of disease observed in the affected individuals (PMID: 2450378, 25616645, 25196244). This variant occurs at an appreciable frequency in the general population and has been identified in 35/281858 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038121	SCV001363285	uncertain significance	not specified	2019-07-15	criteria provided, single submitter	clinical testing	Variant summary: DSP c.943C>T (p.Arg315Cys) results in a non-conservative amino acid change located in the Spectrin/alpha-actinin repeat (IPR018159) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250466 control chromosomes, predominantly at a frequency of 0.00087 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 87 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.943C>T has been reported in the literature in individuals affected with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), dilated cardiomyopathy and Brugada syndrome (Bhonsale_2015, Chen_2018, Walsh_2017, Zhao_2016). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Co-occurrences with pathogenic variants in VCL (c.1639C>T, p.Arg547*) and SCN5A (c.3823G>A, p.Asp1275Asn) genes have been reported in two patients affected with dilated cardiomyopathy and Brugada syndrome, respectively (Pugh_2014, Zhang_2016). Additionally, a co-occurrence with a pathogenic DSP variant (c.6478C>T, p.Arg2160*) has been reported in an ARVD/C patient (Bhonsale_2015), providing supporting evidence for a benign role. Results from two recent abstracts presented in scientific conferences from the same group describe the variant to effect DSP binding to CSN6 protein, cardiac CSN6 reduction and early electrical defects found in ARVC in DSP R315C knock-in mice (Liang_2019, Sheikh_2018). The authors highlight the importance of CSN6 at the cardiac desmosome and suggest loss of CSN6 as a new underlying mechanism driving ARVC and sudden death. However, since the role of CSN6 in the cause of ARVC has not been conclusively determined at the time of this classification and these results are not provided in a peer-reviewed, full-text publication, no conclusive interpretations can be drawn. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (6x) and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CeGaT Center for Human Genetics Tuebingen	RCV000766874	SCV004042248	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000038121	SCV000280099	uncertain significance	not specified		no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below, we classify this as a variant of unknown significance (VUS). Mutations in the DSP gene have been reported in at least 7% of patients with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC). Harvard’s LMM has reported this variant in two patients with dilated cardiomyopathy (DCM) who also carried variants in multiple other cardiomyopathy genes. They classified it as a variant of unknown significance (Pugh et al. 2014, Supplementary Data). This is a non-conservative amino acid change from a positively-charged arginine to a polar, uncharged cysteine capable of forming disulfide bonds. The arginine at codon 315 is not conserved across species (it is an arginine in 6 out of 8 vertebrate species, and a leucine in 2 others). In silico analysis with PolyPhen-2 predicts the variant to be “probably damaging” with a score of 1.0. No variants within 10 amino acid residues have been listed in HGMD in association with ARVC (HGMD professional version as of January 17, 2014). The closest is Ser299Arg. In total the variant has been seen in 2 out of ~7500 individuals from population datasets. It was found in 1 Han Chinese individual in 1000 Genomes (1/197 Han Chinese individuals total). It was also seen in 1 Caucasian individual in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of March 27, 2014). The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension.