ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.1787C>T (p.Ala596Val) (rs148185335)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000246946 SCV000318681 likely benign Cardiovascular phenotype 2017-12-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Subpopulation frequency in support of benign classification
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172526 SCV000051373 likely benign not provided 2013-06-24 criteria provided, single submitter research
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770533 SCV000901980 uncertain significance Cardiomyopathy 2016-03-04 criteria provided, single submitter clinical testing
Color RCV000770533 SCV000910999 likely benign Cardiomyopathy 2018-03-09 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000238623 SCV000297175 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2015-08-10 criteria provided, single submitter clinical testing
GeneDx RCV000039412 SCV000233434 uncertain significance not specified 2017-05-03 criteria provided, single submitter clinical testing The A596V variant in the DSC2 gene has also been reported in the literature (den Haan et al., 2009; Tan et al., 2010). den Haan et al. (2009) reported A596V as a benign variant due to its presence in control samples. Tan et al. (2010) identified the A596V variant in one individual with ARVC; however, A596V was also identified in 1/100 control individuals in this study. The A596V variant was observed in approximately 0.1% of alleles from individuals of European ancestry in the NHLBI Exome Sequencing Project, and in approximately 0.6% of alleles from individuals of South Asian ancestry and approximately 0.4% of alleles from individuals of Ad Mixed American ancestry in the 1000 Genomes Project, indicating it may be a rare benign variant in these populations. Although the A596V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, the A596 residue is conserved across species. Consequently, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Integrated Genetics/Laboratory Corporation of America RCV000172526 SCV000699496 likely benign not provided 2017-05-29 criteria provided, single submitter clinical testing Variant summary: The DSC2 c.1787C>T (p.Ala596Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 152/121170 control chromosomes, predominantly observed in the subpopulation at an allele frequency of 0.0029755 (49/16468). This frequency is about 298 times the estimated maximal expected allele frequency of a pathogenic DSC2 variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of origin. This variant has been reported in patients with ARVC, HCM, DCM and SIDS (Tan_2010, Lopes_2013, Santori_2015, Haas_2015, and Bottillo_2016). No cosegregation analysis was performed in these studies. In one patient with HCM, another pathogenic variant MYH7 p.V606M was also detected, indicating benign outcome (Lopes_2013). In ClinVar while two clinical diagnostic laboratories have classified this variant as likely benign, three have classified it as VUS. Taken together, this variant is classified as likely benign.
Invitae RCV000475303 SCV000561694 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 11 2017-12-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000039412 SCV000063096 likely benign not specified 2017-04-07 criteria provided, single submitter clinical testing p.Ala596Val in exon 12 of DSC2: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (49/16468) of South Asian chro mosomes, including 1 homozygous individual, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP dbSNP rs148185335).
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000039412 SCV000740321 likely benign not specified 2016-12-22 criteria provided, single submitter clinical testing

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