ClinVar Genomic variation as it relates to human health

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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, http://exac.broadinstitute.org; dbSNP rs28763965). Computational prediction too ls and conservation analysis do not provide strong support for or against an imp act to the protein.

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 0.0017 in 252108 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 173.34 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. c.4372C>G has been reported in the literature in individuals affected with Arrhythmia, DCM or HCM (Cox_2011, Kapplinger_2011, Pugh_2014, Andreasen_2013, Jaaskelainen_2019). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Co-occurrences with other pathogenic variant(s) have been reported (DSP c.3337C>T, R1113X; CASQ2 c.1090_1091insG, p.Asp364GlyfsX10 ; MYH7 c.3158G>A , p.Arg1053Gln), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 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. Based on the evidence outlined above, the variant was classified as benign.

This variant is associated with the following publications: (PMID: 21606396, 21636032, 25163546, 24503780, 25179549, 25661095, 25637381, 23299917, 23861362, 25569433, 25985138, 26332594, 27153395, 27930701, 27435932, 26743238, 24055113, 28600387, 30403697, 33232181)

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

DSP: BP4, BS1, BS2

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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).