ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.1103C>T (p.Thr368Ile) (rs538663626)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617760 SCV000734936 uncertain significance Cardiovascular phenotype 2017-10-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000644632 SCV000766334 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 368 of the DSC2 protein (p.Thr368Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs538663626, ExAC 0.009%). This variant has not been reported in the literature in individuals with DSC2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786115 SCV000924768 uncertain significance not provided 2017-10-24 no assertion criteria provided provider interpretation Found on postmortem testing of a 17-year-old with a negative autopsy and a history of 2 seizures in one day and then a sudden death a few months later. A 148-gene Arrhythmia and Cardiomyopathy Comprehensive Panel was done by the Invitae laboratory. This included Sudden Death in Epilepsy genes. Results included 3 variants: -p.Thr368Ile (c.1103C>T) in the DSC2 gene -p.Ala647Val (c.1940C>T) in the LAMA4 gene -p.Arg177Cys (c.529C>T) in the MYBPC3 gene p.Thr368Ile (c.1103C>T) in exon 9 of the DSC2 gene (NM_024422.4) Chromosome location 18:28662364 G / A Based on the information reviewed below, including how poorly conserved this amino acid is across vertebrate species, the lack of case data, and the fact that it has been found in the broader population in an individual with our patient’s Latino ancestry, we classify it as a Variant of Uncertain Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing. Of note, Kapplinger et al. (2011) from Mayo Clinic have reported a significant yield of rare missense variants in the ARVC genes of presumably healthy controls from various ethnicities. According to their data, 16% of 427 controls hosted missense variants—similar to the 21% yield in 175 Dutch and U.S. ARVC cases. This is a reminder that missense variants of unknown significance in ARVC-related genes need to be interpreted with particular caution. This variant has not been reported in the literature in association with disease. Of note, the majority of Likely Pathogenic and Pathogenic variants in this gene that have been reported to ClinVar are truncating (nonsense, frameshift, or splice site) and are not missense variants like this one. This is a nonconservative amino acid change, resulting in the replacement of a polar Threonine with a nonpolar Isoleucine in the extracellular domain of the protein. Threonine at this location is poorly conserved across ~100 vertebrate species for which we have data. It is frequently a positively-charged Arginine, a positively-charged Lysine, or a negatively-charged Glutamic Acid. The default amino acid is Isoleucine in at least 2 species. There are no convincingly Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. Liu et al. (2017) report that a nearby variant segregated with ARVC in a Chinese family across 3 meioses (p=0.125). According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant was reported in 1 out of 16,776 Latino individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Overall minor allele frequency (MAF) = 0.0004%. Latino MAF = 0.003%. Our patient’s ancestry is Latino. The phenotype of the individuals in gnomAD 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. The curators made an effort to exclude individuals with severe pediatric diseases.

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