ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.5513G>A (p.Arg1838His) (rs377715841)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181329 SCV000233626 uncertain significance not specified 2014-05-14 criteria provided, single submitter clinical testing The R1838H variant in the DSP gene has been reported in one individual with DCM who also harbored a R907H variant in DSP (Garcia - Pavia P et al., 2011). This individual's parent, who also harbored the R1838H variant, had DCM with fatty infiltrate and fibrosis in the right ventricle. The authors did not report whether the parent harbored R907H. Additionally, R1838H was identified on whole genome sequencing in one individual with a family history of vascular disease and early sudden death (Ashley E et al., 2010). This individual had two other rare variants identified in the TMEM43 and MYPBC3 genes. Furthermore, R1838H was observed in only 3/8600 alleles from individuals of European ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In silico algorithms are not consistent in their predictions but at least two concur that R1838H is damaging to the protein structure/function. However, R1838H is only a conservative amino acid substitution as these residues share similar properties, and are least likely to impact secondary structure. The R1838 residue is not well conserved across species, and definitive mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000381747 SCV000465126 likely benign Ectodermal dysplasia skin fragility syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000296688 SCV000465127 likely benign Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000351218 SCV000465128 likely benign Epidermolysis bullosa, lethal acantholytic 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000391247 SCV000465129 likely benign Skin fragility woolly hair syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000458538 SCV000543284 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1838 of the DSP protein (p.Arg1838His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs377715841, ExAC 0.01%). This variant has been reported in the literature in an individual affected with dilated cardiomyopathy (PMID: 21859740), in individuals affected with arrythmogenic right ventricular cardiomyopathy (PMID: 28471438), and in an individual with a family history of vascular disease and sudden death (PMID: 20435227). ClinVar contains an entry for this variant (Variation ID: 161225). 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: "Possibly Damaging"; 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.
Color RCV000777694 SCV000913627 uncertain significance Cardiomyopathy 2018-10-26 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the coiled coil rod domain of the DSP protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy(PMID: 21859740), arrhythmogenic cardiomyopathy (PMID: 28288337) and sudden cardiac death (PMID: 20435227). This variant has been identified in 21/277092 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
CSER_CC_NCGL; University of Washington Medical Center RCV000148475 SCV000190176 likely benign Primary dilated cardiomyopathy 2014-06-01 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.