ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.7622G>A (p.Arg2541Lys) (rs142078450)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000218025 SCV000271742 uncertain significance not specified 2015-05-27 criteria provided, single submitter clinical testing The p.Arg2541Lys variant in DSP has been reported in 1 individual with ARVC (Bau ce 2010, Bauce 2011, Rigato 2013). The variant segregated with disease in 3 affe cted family members (including 2 obligate carriers); however, another affected r elative did not carry the variant (Bauce 2010). This variant has been identified in 3/66740 European chromosomes by the Exome Aggregation Consortium (ExAC, http ://; dbSNP rs142078450). Arginine (Arg) at position 2541 is not conserved evolution and 4 mammals carry a lysine (Lys), suggesting that t his change may be tolerated. In summary, the clinical significance of the p.Arg2 541Lys variant is uncertain due to conflicting data.
Illumina Clinical Services Laboratory,Illumina RCV000278298 SCV000465210 uncertain significance Epidermolysis bullosa, lethal acantholytic 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000335658 SCV000465211 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 8 2016-07-27 criteria provided, single submitter clinical testing The DSP c.7622G>A (p.Arg2541Lys) variant is a missense variant that has been reported in four studies, where it was found in six individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC), including in a compound heterozygous state in two individuals and in a heterozygous state in four (Bauce et al. 2010; Bauce et al. 2011; Rigato et al. 2013; Zorzi et al. 2015). The variant was also found in three unaffected individuals from the family described in Bauce et al. (2010); these individuals ranged in age from 20 to 30 years. Their unaffected status could represent decreased penetrance due to their ages. In the same family, of the three known or obligate carriers of the variant, one suffered sudden death at age 45, one affected female died of heart failure at age 64, and one was diagnosed at age 37. Zorzi et al. (2015) conducted a follow-up study and evaluated data from the individuals described by Rigato et al. (2013); one individual with this variant experienced cardiac arrest. The p.Arg2541Lys variant was absent from over 1100 control alleles but is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg2541Lys variant is classified as a variant of unknown significance but suspicious for pathogenicity for arrhythmogenic right ventricular cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Clinical Services Laboratory,Illumina RCV000378413 SCV000465212 uncertain significance Skin fragility woolly hair syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000286314 SCV000465213 uncertain significance Ectodermal dysplasia skin fragility syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000814505 SCV000954918 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 2541 of the DSP protein (p.Arg2541Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs142078450, ExAC 0.004%). This variant has been observed in several individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24070718, 20129281). ClinVar contains an entry for this variant (Variation ID: 228649). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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