ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.3338G>A (p.Arg1113Gln) (rs768455823)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000531336 SCV000641305 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-03-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1113 of the DSP protein (p.Arg1113Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs768455823, ExAC 0.06%) but 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786120 SCV000924781 uncertain significance not provided 2017-03-29 no assertion criteria provided provider interpretation Given that there are no cases reported in the literature with this variant and the limited evidence that missense variation is a mechanism of pathogenicity in this gene, we consider this variant a variant of uncertain signifiance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There is no case data available on this variant. This variant is not present in ClinVar. It is currently unclear what role, if any, missense variation in DSP has in cardiomyopathy: 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. 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. This is a reminder that missense variants of unknown significance in ARVC-related genes need to be interpreted with caution. This variant is located outside of the "hot spot" of pathogenic variation in DSP (amino acids 250-604). The arginine at codon 1113 is conserved across species, as are neighboring amino acids. The variant was reported online in 11 of 122,391 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 9 of 8,607 individuals of East Asian descent (MAF=0.05%) and 2 of 15,354 individuals of South Asian descent. The phenotype of those individuals is not publicly available. Additional variants at codon 1113 are present in gnomAD: p.Arg1113Gly is present in 1 out of 12,763 individuals of Latino descent and p.Arg1113Arg (c.3338G>T) is present in 1 out of 7,554 individuals of African descent. 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 datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).

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