ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.5324G>T (p.Arg1775Ile) (rs34738426)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000148479 SCV000050924 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2013-06-24 criteria provided, single submitter research
CSER_CC_NCGL; University of Washington Medical Center RCV000148479 SCV000190181 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2014-06-01 no assertion criteria provided research
Fulgent Genetics,Fulgent Genetics RCV000764660 SCV000895786 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8; Epidermolysis bullosa, lethal acantholytic; Skin fragility woolly hair syndrome; Keratosis palmoplantaris striata II; Cardiomyopathy, dilated, with woolly hair, keratoderma, and tooth agenesis 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000766884 SCV000233686 uncertain significance not provided 2018-11-21 criteria provided, single submitter clinical testing The R1775I variant of uncertain significance in the DSP gene has been previously reported in association with ARVC (Bauce et al., 2005; Bauce et al., 2011). Bauce et al. (2005) first reported R1775I in one Italian female diagnosed with ARVC at 37 years of age, which segregated with regional RV abnormalities in one relative, and with late potentials found on SAECG in a second relative. In a second study, Bauce et al. (2011) described R1775I in two Italian pediatric individuals identified through family screening, including one individual who harbored an additional cardiogenetic variant; however, data was unavailable to confirm whether these individuals were affected or if one of these carriers may be related to the family described in Bauce et al. (2005). The R1775I variant is classified as a variant of uncertain significance in ClinVar by a different clinical laboratory (ClinVar SCV000271733.1; Landrum et al., 2016), and has been observed in one heterozygous individual with woolly hair who was referred for exome sequencing at GeneDx, although no cardiac-related clinical information or informative segregation data is available. The R1775I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. The R1775I variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, or with any significant frequency in the 1000 Genomes Project, indicating it is not a common benign variant in these populations. Nevertheless, this variant has been identified in 1/1734 (0.05%) alleles from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death (Ng et al., 2013), although a follow-up cardiac exam for the individual carrying this variant was not reported. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000460497 SCV000543250 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-07-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with isoleucine at codon 1775 of the DSP protein (p.Arg1775Ile). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and isoleucine. This variant is present in population databases (rs34738426, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 15941723). ClinVar contains an entry for this variant (Variation ID: 161227). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000215521 SCV000271733 uncertain significance not specified 2014-12-31 criteria provided, single submitter clinical testing The p.Arg1775Ile variant in DSP has been previously reported in 1 adult with sud den death and segregated with right ventricular and ECG abnormalities in 2 affec ted family members (Bauce 2005). This variant has also been identified in 8/1655 6 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs34738426). The affected amino acid is not well cons erved in evolution, raising the possibility that a change may be tolerated; howe ver, this is not predictive enough to rule out pathogenicity. In summary, the cl inical significance of the p.Arg1775Ile variant is uncertain.
SIB Swiss Institute of Bioinformatics RCV000677333 SCV000803592 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Arrhythmogenic right ventricular dysplasia 8, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1-Supporting => BS1 downgraded in strength to supporting.

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