ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.3706A>G (p.Arg1236Gly) (rs377098318)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000641769 SCV000763417 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 1236 of the DSP protein (p.Arg1236Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs377098318, ExAC 0.09%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 534277). 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: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786121 SCV000924782 uncertain significance not provided 2018-01-03 no assertion criteria provided provider interpretation Variant p.Arg1236Gly c.3706A>G in exon 23 of DSP (NM_004415.2, hg19 chr6-7580129-A-G) SCICD classification Variant of uncertain significance. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: lack of case data. Gene-level evidence DSP: Variants in DSP are associated with several disorders. Heterozygous variants in DSP can cause arrhythmogenic right ventricular cardiomypathy (ARVC) and arrhytmogenic cardiomyopathy with left-sided disease. Homozygous or compound heterozygous variants (inherited in an autosomal recessive manner) cause Carvajal syndrome. Features of Carvajal include cardiomyopathy, arrhythmias and ectodermal findings like wooly hair and keratoderma. Both truncating and missense variants in DSP can cause disease, but require a thorough variant review due to hig prevelance of missense variants in DSP in the general population. Case data summary Not reported in the literature. Not listed in ClinVar. Predicted Consequence Per the test report, "The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine." Experimental Data None reported In silico data Per 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: "Deleterious"; PolyPhen-2: "Benign"; Align- GVGD: "Class C0")." Conservation Per the test report, "The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine." The arginine at position 1236 is conserved in 88 of 100 total aligned species in the UCSC genome browser. Nearby pathogenic variation None at this codon. None at neighboring codons. Population Data Highest MAF in African population: 0.075% Please see below for details. Population data for p.Arg1236Gly: Highest MAF in African population: 0.075%. The variant was reported online in 20 of 138,271 total individuals (MAF: 0.0072%) 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, and Latino descent. Specifically, the variant was observed in: 18 of 11,968 individuals of African descent (MAF=0.075%) 1 of 63,109 individuals of non-Finnish European descent (MAF=0.00079%) 1 of 17,200 individuals of Latino descent (MAF=0.0029%) The phenotype of those individuals is not publicly available. The dataset is composed of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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