ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.1696G>A (p.Ala566Thr) (rs148147581)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617402 SCV000738242 uncertain significance Cardiovascular phenotype 2017-12-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000735747 SCV000863904 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-06-18 no assertion criteria provided clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148476 SCV000190178 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2014-06-01 no assertion criteria provided research
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626864 SCV000747567 uncertain significance Palmoplantar blistering; Skin fragility with non-scarring blistering 2017-01-01 criteria provided, single submitter clinical testing
Color RCV000771793 SCV000904482 uncertain significance Cardiomyopathy 2018-04-08 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the plakin domain of the DSP 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 does not cause significant changes in EB1 binding or Cx43 membrane localization (PMID 25225338). While this variant has been reported in several individuals affected with arrhythmogenic left ventricular cardiomyopathy (PMID: 16774985, 22949226, 21606396), it has also been identified in 53/276746 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Fulgent Genetics,Fulgent Genetics RCV000515316 SCV000611474 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8; Epidermolysis bullosa, lethal acantholytic; Skin fragility woolly hair syndrome; Keratosis palmoplantaris striata II; Cardiomyopathy, dilated, with woolly hair, keratoderma, and tooth agenesis 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000766877 SCV000233584 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing The A566T variant of uncertain significance in the DSP gene has been reported previously in association with ARVC and as an unclassified variant (Basso et al., 2006; Cox et al., 2011). This variant has also been reported in association with hypertrophic cardiomyopathy (Lopes et al., 2015) and DCM (Franaszcyk et al., 2017). Basso et al. (2006) initially identified A566T in one patient with ARVC who also harbored another variant in the DSP gene. Cox et al. (2011) subsequently reported A566T as an unclassified variant identified in a patient with ARVC. This variant is observed in 40/126324 (0.03%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The A566T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammalian species. However, functional studies suggest that the A566T variant alone is insufficient to impair protein function (Patel et al., 2014). Furthermore, only one missense variant in nearby a residue (T564I) has been reported in the Human Gene Mutation Database (Stenson et al., 2014) in association with Naxos-Carvajal syndrome; however, the full significance of this variant is unknown.
Illumina Clinical Services Laboratory,Illumina RCV000284191 SCV000464898 likely benign Epidermolysis bullosa, lethal acantholytic 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000148476 SCV000464899 likely benign Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000403225 SCV000464900 likely benign Ectodermal dysplasia skin fragility syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000285554 SCV000464901 likely benign Skin fragility woolly hair syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000476727 SCV000543275 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-03-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 566 of the DSP protein (p.Ala566Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs148147581, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in several individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 16774985, 22949226, 21606396). ClinVar contains an entry for this variant (Variation ID: 161226). Experimental studies have shown that this missense change does not significantly alter DSP activity in an in vitro proximity ligation assay, but the clinical significance of this observation is uncertain (PMID: 25225338). In summary, this variant has been seen in several individuals with arrhythmogenic right ventricular cardiomyopathy. However, it has been observed at an elevated frequency in control population datasets compared to DSP-related diseases, and was shown to not have an effect in a functional assay. In the absence of conclusive evidence at this time, this missense change has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000150560 SCV000197800 likely benign not specified 2017-12-05 criteria provided, single submitter clinical testing p.Ala566Thr in exon 13 of DSP: This variant is not expected to have clinical sig nificance because it has been identified in 0.03% (40/126324) of European chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute .org; dbSNP ${MatchVariant_1_dbSNPrsNumber}). ACMG/AMP Criteria applied: BS1.

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