ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.269A>G (p.Gln90Arg) (rs188516326)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000150556 SCV000197787 uncertain significance not specified 2015-02-18 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Gln90Arg vari ant in DSP has been identified in 0.9% (75/8002) of East Asian chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs18 8516326). At this frequency a disease causing role is highly unlikely. However, published data appears to favor a role in disease although there is some concer n regarding the validity of the claims made by the authors. This variant has bee n reported in at least 1 individual with ARVC who carried a frameshift variant i n PKP2 that would be expected to contribute to disease (Yang 2006, Xu 2010, Cox 2011 - note that there is some suspicion that the same individual was reported b y all 3 studies). One of these studies claimed de novo occurrence of the p.Gln90 Arg variant (without providing information on verification of paternity) and dis qualified the (more convincing) PKP2 variant based on its presence in two unaffe cted relatives (Xu 2010). In vitro functional studies showed that this variant may impact protein function (Yang 2006), though this type of assay may not accur ately represent biological function. In summary, the frequency of the p.Gln90Arg variant strongly suggests that it is more likely to be benign; however, due to the strongly conflicting published data additional information is needed to ful ly assess its clinical significance.
GeneDx RCV000150556 SCV000233558 uncertain significance not specified 2016-12-14 criteria provided, single submitter clinical testing The Q90R variant of uncertain significance in the DSP gene has been reported previously in association with ARVC (Yang et al., 2006; Xu et al., 2010; Cox et al., 2011). Q90R was identified in a patient with ARVC and functional studies revealed this variant failed to localize to the cell membrane, which disrupted normal protein binding (Yang et al., 2006). Xu et al. (2010) subsequently identified Q90R as a de novo variant in an individual with ARVC who also harbored a PKP2 frameshift variant. Nevertheless, Cox et al. (2011) reported Q90R as an unclassified variant, which was identified in one individual with ARVC. Furthermore, one other clinical laboratory classifies Q90R as a variant of uncertain significance (SCV000197787.2; Landrum et al., 2016). Additionally, the 1000 Genomes Project and the Exome Aggregation Consortium (ExAC) report Q90R was observed with an allele frequency of 0.5-0.9% in individuals of Eastern Asian ancestry, indicating it may be a rare benign variant in this population.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or a rare benign variant in individuals of Asian ancestry.
Illumina Clinical Services Laboratory,Illumina RCV000335027 SCV000464842 likely benign Epidermolysis bullosa, lethal acantholytic 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000397112 SCV000464843 likely benign Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000313888 SCV000464844 likely benign Skin fragility woolly hair syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000370851 SCV000464845 likely benign Ectodermal dysplasia skin fragility syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000462579 SCV000555774 benign Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-09-27 criteria provided, single submitter clinical testing
Color RCV000771368 SCV000903663 benign Cardiomyopathy 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000150556 SCV000919296 likely benign not specified 2018-12-26 criteria provided, single submitter clinical testing Variant summary: DSP c.269A>G (p.Gln90Arg) results in a conservative amino acid change located in the JUP/PKP binding domain (Yang_2006) of 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. 0.00072 in 281004control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.0092 including 1 homozygote (gnomAD and publication data). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 46-fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.0002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.269A>G, has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and sudden death but also in controls (Yang_2006, Zhang_2016, Cox_2011). Co-occurrences with other pathogenic variant(s) have been reported (c.1211dupT (p.Val406fsX4)), providing supporting evidence for a benign role (Xu_2010, Cox_2011). One publication reports experimental evidence showing that the variant protein was mainly detected in the cytoplasm and did not accumulate at cell membranes (or cell junctions), with two transgenic founder mice showing severely reduced ventricular wall thickness (Yang_2006). Another study showed that this variant does not affect the binding of the iASPP protein (Notari_2015). The clinical significance of these in-vitro and in-vivo studies is not clear. Five 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 (VUS x3, likely benign x1, benign x1). Based on the evidence outlined above, the variant was classified as likely benign.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000150556 SCV000280087 uncertain significance not specified 2015-09-21 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 weak case data, presence in controls, and presence of a more convincing variant in one of the reported cases, we consider this variant to be a variant of uncertain significance, probably benign. The variant has been seen in at least 2 unrelated cases of ARVC). Yang et al (2006) reported the variant in 1 of 66 individuals in the North American ARVD registry. The same group later reported a patient with this variant and a frameshift in PKP2 (Xu et al 2010). Presumably these are the same patient, though insufficient data is reported to assess that. A British group observed the variant in 1 of 149 ARVC probands in their cohort (Cox et al 2011). Ancestry data was not provided in either report. In silico analysis with PolyPhen-2 predicts the variant to be benign. In total the variant has been seen in 5 of 6972 published controls and individuals from publicly available population datasets. The variant is present in 5 of 544 alleles (likely 5/272 individuals) from Asian individuals in the 1000 genomes sample. There is no variation at codon 90 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of May 16th, 2014). The variant was not observed in the following laboratory and published control samples: 200 individuals (Yang et al 2006).

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