ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.304G>A (p.Glu102Lys) (rs144799937)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000248994 SCV000320061 uncertain significance Cardiovascular phenotype 2017-12-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence,Insufficient evidence
Blueprint Genetics RCV000039432 SCV000206894 likely benign not specified 2015-11-27 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769503 SCV000900898 likely benign Cardiomyopathy 2017-10-02 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148467 SCV000190167 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-10-01 criteria provided, single submitter research Found in 2 unrelated patients 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.
Color RCV000769503 SCV000902951 likely benign Cardiomyopathy 2018-08-06 criteria provided, single submitter clinical testing Likely Benign based on current evidence: This missense variant is located in the N-terminal propeptide sequence of the DSC2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. An experimental study has shown that this variant may cause the protein to localize to the cytoplasm in addition to the cell-cell junction (PMID: 17963498). However, biological significance of this finding is unknown. This variant has been reported in individuals with arrhythmogenic, dilated and hypertrophic cardiomyopathy (PMID: 17963498, 20197793, 21606390, 23147450, 23396983) but has also been detected in unaffected family members (PMID: 17963498, 23147450). This variant is common in the general population and has been identified in 156/126324 non-Finnish European chromosomes (0.12%) and 21/10134 Ashkenazi Jewish chromosomes (0.21%) by the Genome Aggregation Database (gnomAD). This variant allele frequency is greater than expected for the disorder based on prevalence, penetrance, and genetic heterogeneity. Based on collective evidence, this variant is classified as Likely Benign.
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000232838 SCV000733781 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 11 no assertion criteria provided clinical testing
GeneDx RCV000039432 SCV000233412 likely benign not specified 2018-03-05 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000232838 SCV000743499 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 11 2017-07-28 criteria provided, single submitter clinical testing
Invitae RCV000232838 SCV000290736 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-01-26 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000039432 SCV000063116 uncertain significance not specified 2018-08-16 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Glu102Lys var iant in DSC2 has been reported in 5 individuals with ARVC (Beffagna 2007, Quarta 2011, Anastasakis 2012) and 2 individuals with LVNC (Miszalski-Jamka 2017). It was also identified by our laboratory in 6 individuals (1 with SCA, 1 with HCM, 1 with ARVC and 3 with DCM (1 of whom carries a likely pathogenic variant in MYB PC3)). This variant has been identified in 0.1% (156/126324) of European chromos omes and 0.2% (21/10134) of Ashkenazi Jewish chromosomes by the Genome Aggregati on Database (gnomAD, http://exac.broadinstitute.org). In vitro functional studie s suggest that the p.Glu102Lys variant may disrupt proper localization of the pr otein (Beffagna 2007); however, these types of assays may not accurately represe nt biological function. Glutamic acid (Glu) at position 102 is not conserved in mammals or evolutionarily distant species and 1 mammal (pika) carries a Lysine ( Lys) at this position, raising the possibility that this change may be tolerated . Additional computational prediction tools also suggest that the p.Glu102Lys va riant may not impact the protein, though this information is not predictive enou gh to rule out pathogenicity. In summary, while the clinical significance of the p.Glu102Lys variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting, BP4, PS3_Supporting.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000039432 SCV000280078 uncertain significance not specified 2014-12-07 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. Given the variant has been observed in disparate phenotypes and is present with an MAF >0.1% in samples unselected for ARVC, we consider this variant a variant of uncertain significance. The variant has been reported in the literature in at least 5 individuals with ARVC (Beffagna 2007, De Bertoli et al 2010, Quarta 2011, Anastasakis 2012). Per the LMM ClinVar submission: "In vitro functional studies suggest that the p.Glu102Lys variant may disrupt proper localization of the protein (Beffagna 2007). However, these types of assays may not accurately represent biological function. Glutamic acid (Glu) at position 102 is not conserved in mammals or evolutionarily distant species and 1 mammal (pika) carries a Lysine (Lys) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools also suggest that the p.Glu102Lys variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity." The variant was reported online in 89 of 60,526 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 22nd, 2015). Specifically, the highest frequency was in Europeans with 71/33283 (MAF 0.11%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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