ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.4372C>G (p.Arg1458Gly) (rs28763965)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172538 SCV000051385 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038041 SCV000061707 likely benign not specified 2017-04-07 criteria provided, single submitter clinical testing p.Arg1458Gly in exon 23 of DSP: This variant is not expected to have clinical si gnificance because it has been identified in 0.36% (41/11544) of Latino and 0.24 % (159/66436) of European chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs28763965). Computational prediction too ls and conservation analysis do not provide strong support for or against an imp act to the protein.
GeneDx RCV000038041 SCV000233618 uncertain significance not specified 2017-10-10 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The R1458G variant has been previously reported in multiple individuals with a range of cardiac phenotypes including ARVC, DCM and BrS (Kapplinger et al., 2011, Cox et al, 2011; Adler et al., 2016; Golbus et al., 2014; Pugh et al., 2014; Haas et al., 2015; Marquez et al., 2015), as well as in cases of autopsy-negative sudden unexplained death (SUD) and sudden infant death syndrome (SIDS) (Methner et al., 2016; Sanchez et al., 2016). However, most of these published individuals also harbored additional cardiogenetic variants and no informative segregation data is available to further clarify the role of this variant in disease. Furthermore, this variant has been identified in multiple individuals who underwent whole exome or genome sequencing for indications unrelated to cardiomyopathy or arrhythmia (Ng et al., 2013; Jurgens et al. 2015; Taylor et al., 2015; Maxwell et al. 2016). Additionally, the R1458G variant has been observed in 41/11544 (0.36%) alleles from individuals of Latino ancestry, and in 159/66436 (0.24%) alleles from individuals of Non-Finnish European ancestry, including one homozygous individual, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1458G 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. In addition, this substitution occurs at a position that is conserved in mammals. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000172538 SCV000288536 likely benign not provided 2019-02-24 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000238741 SCV000297158 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2015-10-19 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000238741 SCV000465030 likely benign Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000368914 SCV000465031 likely benign Epidermolysis bullosa, lethal acantholytic 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000397854 SCV000465032 likely benign Skin fragility woolly hair syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000315105 SCV000465033 likely benign Ectodermal dysplasia skin fragility syndrome 2016-06-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000622004 SCV000734867 likely benign Cardiovascular phenotype 2018-12-30 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification;In silico models in agreement (benign)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000038041 SCV000883752 likely benign not specified 2018-11-06 criteria provided, single submitter clinical testing
Color RCV000771820 SCV000904525 likely benign Cardiomyopathy 2018-03-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000038041 SCV000917290 likely benign not specified 2018-07-30 criteria provided, single submitter clinical testing Variant summary: DSP c.4372C>G (p.Arg1458Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 277828 control chromosomes in the gnomAD database and publications, including 1 homozygotes. The observed variant frequency is approximately 166-fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. The variant, c.4372C>G, has been reported in the literature in individuals affected with ARVD and DCM (Cox_2011, Kapplinger_2011, Pugh_2014), however co-occurrences with other pathogenic variant(s) have been reported in these publications (DSP c.3337C>T/R1113X, CASQ2 c.1090_1091insG/p.Asp364GlyfsX10), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (4x likely benign, 2x VUS). Based on the evidence outlined above, the variant was classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845543 SCV000987661 uncertain significance Familial dilated cardiomyopathy criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000771820 SCV000995744 likely benign Cardiomyopathy 2017-11-01 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000172538 SCV001154643 uncertain significance not provided 2019-06-01 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148477 SCV000190179 uncertain significance Arrhythmogenic right ventricular dysplasia/cardiomyopathy 2014-06-01 no assertion criteria provided research
Blueprint Genetics RCV000157197 SCV000206921 uncertain significance Left ventricular noncompaction cardiomyopathy 2014-07-10 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000038041 SCV000280088 uncertain significance not specified 2014-12-02 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. We classify this as a variant of uncertain significance, based on the weak case data, presence of another more convincing variant in one of the cases, and the presence in control or general populations samples. The variant has been seen in at least one case of DCM and one case of ARVC. There is no segregation data available. Cox et al (2010) reported the variant in one of 149 probands with ARVC in their Dutch cohort. In the paper it appears that this is the only variant the patient had in the five desmosomal genes sequenced, however in an online database managed by one of the authors it is noted that the patient also carries a nonsense variant in DSP that they consider pathogenic. This is likely the same case included in Kapplinger et al (2011) since both are from a Dutch cohort with the same authors. Pugh et al (2014) observed the variant in one patient in a cohort of 766 patients with "DCM or clinical features consistent with DCM" who had genetic testing performed at the Lab for Molecular Medicine. The patient also carries variant of uncertain significance in TTN, CASQ2, ACTN2, and ABCC9. Both of these groups classified the variant as a variant of uncertain significance. In total the variant has been seen in 26 o f 7973 published controls and individuals from publicly available population datasets. The highest frequency is 2 of 173 individuals within the 1000 genomes dataset. The variant was reported online in 18 of 4300 Caucasian individuals and 4 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of April 22nd, 2014). Another variant at the same codon, p.Arg1458Gln, is present in 28 of 4300 Caucasian individuals and 0 of 2203 African-American individual. 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. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). Per the GeneDx report, the variant was observed in 2 of 173 individuals in the 1000 Genomes project and those individuals are Hispanic. The ClinSeq group reported that they observed the variant in 2 of 870 individuals (Ng et al 2013). The variant was not observed in the following laboratory and published control samples: 427 individuals (Kapplinger et al 2011).

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