ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.6881C>G (p.Ala2294Gly) (rs147000526)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621753 SCV000734930 likely benign Cardiovascular phenotype 2017-12-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Does not segregate with disease in family study (genes with incomplete penetrance)
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171919 SCV000050925 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769239 SCV000900615 uncertain significance Cardiomyopathy 2017-03-01 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148480 SCV000190182 likely benign Arrhythmogenic right ventricular cardiomyopathy 2015-12-01 criteria provided, single submitter research
Color RCV000769239 SCV000913763 likely benign Cardiomyopathy 2018-09-18 criteria provided, single submitter clinical testing
GeneDx RCV000038079 SCV000233642 likely benign not specified 2018-02-28 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.
Illumina Clinical Services Laboratory,Illumina RCV000148480 SCV000465178 likely benign Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000297547 SCV000465179 likely benign Epidermolysis bullosa, lethal acantholytic 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000354784 SCV000465180 likely benign Ectodermal dysplasia skin fragility syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000267252 SCV000465181 likely benign Skin fragility woolly hair syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000474972 SCV000555787 likely benign Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-11-14 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038079 SCV000061745 uncertain significance not specified 2017-01-10 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000148480 SCV000740334 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2017-01-29 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000038079 SCV000280095 uncertain significance not specified 2013-11-26 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 lack of segregation in multiple cases we consider this variant a variant of uncertain significance, probably benign. The variant has been seen in at least 2 unrelated cases of DCM and 4 cases ARVC with failure to segregate in at least 4 cases. At least 7% of patients with autosomal dominant ARVC have been reported to have a mutation in the DSP gene (McNally E et al., 2009). The Ala2294Gly variant has been reported previously in two individuals with dilated cardiomyoapthy (Garcia-Pavia P et al., 2011). One of the probands was a 60 year old male, the other a 51 year old male. No segregation analysis was available. This was a cohort of 95 patients randomly selected from a cohort of 187 patients transplanted for DCM between 1993 and 2007. The authors did sequencing for plakophillin-2 (PKP2), desmoplakin (DSP), desmocollin-2 (DSC2), desmoglein (DSG2) and plakoglobin (JUP). They did not study other DCM genes. Garcia and Monserrat (2010, case presentation) reported this variant was identified in a proband with right ventricular dysfunction, whose father was also affected, but did not carry the variant. The proband carried three other variants in the tested ARVC genes. As part of the authors' review of this variant, they report this variant has been reported in an additional three families (Dr. Van der Zwaag, personal communication). In one of these families, a proband with ARVC had solely this variant and it failed to segregate with disease in the proband's mother who also had a clinical diagnosis of ARVC. Another family, the proband (72 years old) carried a second confirmed pathogenic mutation in DSP. In the third family, the variant was identified in the father of a male patient who died suddenly at age 25, although the patient did not have the variant and both were carrier of a confirmed pathogenic mutation in another gene. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The alanine at codon 2294 is conserved across species, as are neighboring amino acids. In total the variant has been seen in 3/6703 laboratory controls, published controls and individuals from publicly available population datasets. The variant was reported online in 3 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of 1/30/14). 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. This variant is listed in dbSNP: rs147000526. The variant was not observed in the following laboratory and published control samples: Not present in 200 control individuals (Garcia-Pavia P e al., 2011)

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