ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.5353G>A (p.Glu1785Lys) (rs528041468)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000551360 SCV000641318 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-05-12 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1785 of the DSP protein (p.Glu1785Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DSP-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786126 SCV000924788 uncertain significance not provided 2017-05-16 no assertion criteria provided provider interpretation p.Glu1785Lys (c.5353G>A) in exon 23 of the DSP gene (NM_004415.2; chr6-7581776-G-A) Given that this variant has not been reported in the literature, the frequency of missense variation in DSP in controls, and its rarity in population databases, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has not been reported in the literature. Kapplinger et al. (2011) from Michael Ackerman’s group have reported a significant yield of rare missense variants in the ARVC genes of presumably healthy controls from various ethnicities. According to their data, 16% of 427 controls hosted missense variants—similar to the 21% yield in 175 Dutch and U.S. ARVC cases. This is a reminder that missense variants of unknown significance in ARVC-related genes need to be interpreted with caution. Kapplinger et al. also report a “hot spot” for DSP variants between amino acids 250-604 in patients with ARVC but not in controls. Walsh et al (2016) found that truncating DSP variants were enriched in cases of DCM over ExAC controls with odds ration of 41.0. There was not significant enrichment of DSP missense variants in DCM cases. DSP truncating variants were also enriched in ARVC cases vs. ExAC controls with odds ratio of 89.9. DSP missense variants were only slightly enriched in cases of ARVC vs. ExAC controls with odds ratio of 2.1. According to the test report, "algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). The glutamic acid at codon 1785 is conserved across species, as are neighboring amino acids. No other variants at this codon or around this codon have been associated with disease. The variant was reported online in 1 of 122,361 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 15,357 individuals of South Asian descent (MAF=0.003%). 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.

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