ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.273+5G>A (rs200473206)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000150557 SCV000197788 uncertain significance not specified 2017-08-11 criteria provided, single submitter clinical testing The c.273+5G>A variant in DSP has been reported in 1 individual with adolescent- onset VT, 1 individual with DCM, 1 individual with sinus bradycardia, 1 compound heterozygous individual with unspecified cardiomyopathy, and at least 3 individ uals with ARVC (Basso 2006, Bauce 2011, Dal Ferra 2017, Mezzano 2016, Rigato 201 3, te Rijdt 2017, LMM data). This variant has also been reported in ClinVar (Var iation ID 163237) and has been identified in 68/125966 European chromosomes by t he Genome Aggregation Database (gnomAD,; dbSNP rs200473206). This variant is located in the 5' splice region. Computational too ls suggest a possible impact to splicing. However, analysis of RNA from patient s carrying this variant did not identify aberrant transcripts (Basso 2006), whic h may indicate that splicing is not impacted. Alternatively, this may be the res ult of RNA degradation, which is a frequent consequence of abnormal splicing. In summary, the clinical significance of the c.273+5G>A variant is uncertain.
GeneDx RCV000589518 SCV000233561 uncertain significance not provided 2018-08-31 criteria provided, single submitter clinical testing The c.273+5 G>A variant of uncertain significance in the DSP gene has been reported previously in association with ARVC and arrhythmia (Basso et al., 2006; Bauce et al., 2011; Mezzano et al., 2016). Basso et al. (2006) identified c.273+5 G>A (reported as c.542+5 G>A using alternate nomenclature) in one individual with ARVC and Bauce et al. (2011) reported c.273+5 G>A in two individuals with ARVC under 18 years of age. Mezzano et al. (2016) identified c.273+5 G>A in a 19 year old male with marked sinus bradycardia and isolated ventricular ectopies. In addition, the c.273+5 G>A variant has been observed in 68/125,966 (0.05%) alleles from individuals of European (non-Finnish) ancesrty in large population cohorts (Lek et al., 2016). In silico analysis using several splice algorithms predicts that this variant destroys the natural splice donor site in intron 2, which is predicted to cause abnormal gene splicing. Consequently, this variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined.
Invitae RCV000232421 SCV000288532 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-12-26 criteria provided, single submitter clinical testing This sequence change falls in intron 2 of the DSP gene. It does not directly change the encoded amino acid sequence of the DSP protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs200473206, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in a family with clinical features of Carvajal syndrome (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has also been observed in individuals affected with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy or sudden infant death syndrome (PMID: 16774985, 21723241, 28074886). This variant is also known as c.542+5G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 163237). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000239152 SCV000297154 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2015-08-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589518 SCV000698427 uncertain significance not provided 2017-01-09 criteria provided, single submitter clinical testing Variant summary: The DSP c.273+5G>A variant involves the alteration of a conserved intronic nucleotide. Mutation Taster predicts a damaging outcome for this variant. 4/4 splice prediction tools predict a significant impact on normal splicing. This variant was found in 39/111734 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000555 (34/61262). This frequency is about 22 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.000025), suggesting this may be a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. However, this variant was absent from 400 healthy controls from published sources (Basso_2006, Bauce_2011, Rigato_2013). In addition, caution has to be taken while using ExAC data as the database includes various large well-phenotyped cohorts (example: Jackson Heart Study, Myocardial Infarction Genetics Consortium, etc.) and no phenotypic information about the individuals who had this variant is provided. Basso et al 2006 detected this variant in one patient with ARVC. They did not find abnormal transcripts in patients cells but hypothesized that the aberrant transcripts may be rapidly degraded through nonsense-mediated decay. Bauce et al 2011 and Rigato et al 2013 detected this variant in three subjects from a cohort of subjects positive for desmosomal variants from ARVC families. However, specific clinical features of the c.273+5G>A variant carriers were not provided. Finally, Mangoni et al 2016 found this variant in a patient with reduced mean heart rate and presenting frequent SAN (sino-atrial node) pauses. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Taken together, this variant is currently classified as variant of uncertain significance (VUS).
Color RCV000776291 SCV000911583 uncertain significance Cardiomyopathy 2018-10-10 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant (also known as c.542+5G>A in the literature) occurs close to intron 2 canonical splice donor site of the DSP gene. Computational splicing tools suggest that this variant may impact RNA splicing. An RNA study performed with cells from a carrier has not detected aberrant transcripts and showed only the wild-type transcript (PMID: 16774985). This observation may be the result of degradation of the aberrant transcripts or may indicate that the variant does not impact splicing. This variant has been reported in three individuals affected with arrhythmogenic right ventricular cardiomyopathy PMID: 16774985, 21723241). This variant has also been identified in 79/275742 chromosomes (68/125966 non-Finnish European chromosomes, 0.054%) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000589518 SCV001154622 uncertain significance not provided 2019-01-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000157211 SCV000206935 uncertain significance Primary dilated cardiomyopathy; Long QT syndrome 2014-09-29 no assertion criteria provided clinical testing
Blueprint Genetics RCV000157212 SCV000206936 uncertain significance Primary dilated cardiomyopathy 2014-09-29 no assertion criteria provided clinical testing

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