ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.1034A>G (p.Asp345Gly) (rs753855393)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000541681 SCV000641280 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2017-06-29 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 345 of the DSP protein (p.Asp345Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs753855393, ExAC 0.05%). This variant 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on DSP function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786124 SCV000924786 uncertain significance not provided 2017-08-01 no assertion criteria provided provider interpretation Invitae performed testing for this patient. Given the lack of case data, frequency in gnomAD and type of variant, we consider this variant a variant of uncertain significance, probably benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). I could find no reports of this variant in Google or PubMed. 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. It should be noted that few missense variants in DSP are thought to be pathogenic. ExAC constraints indicate this gene is tolerant to missense variation (Z=0.91). The variant has been seen in 12 of 122792 individuals listed 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, Latino, and Ashkenazi descent. The variant has been seen in 10 of 8614 East Asian Individuals (MAF = 0.058%). The site is well covered in ExAC.

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