Submissions for variant NM_004415.4(DSP):c.1351C>T (p.Arg451Cys)

dbSNP: rs1057518309

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001861430	SCV002108109	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 451 of the DSP protein (p.Arg451Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DSP-related conditions. ClinVar contains an entry for this variant (Variation ID: 373259). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg451 amino acid residue in DSP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31194698). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
GeneDx	RCV002284389	SCV002574665	uncertain significance	not provided	2022-03-17	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
GeneDx	RCV000413743	SCV000491839	uncertain significance	not specified	2016-11-18	flagged submission	clinical testing	A novel variant of uncertain significance has been identified in the DSP gene. The R451C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R451C 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. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nonetheless, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, all of which would further clarify pathogenicity.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.