Submissions for variant NM_004415.4(DSP):c.6466dup (p.Arg2156fs)

dbSNP: rs1554108859

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478639	SCV000567336	pathogenic	not provided	2015-07-27	criteria provided, single submitter	clinical testing	Although the c.6466dupA duplications in the DSP gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Arginine 2156, changing it to a Lysine, and creating apremature stop codon at position 9 of the new reading frame, denoted p.Arg2156LysfsX9. This duplication isexpected to result in an abnormal, truncated protein product with the last 716 correct amino acids beingreplaced by 8 incorrect amino acids. Other frameshift variants in the DSP gene have been reported inHGMD in association with cardiomyopathy (Stenson P et al., 2014). Furthermore, the c.6466dupA duplicationwas not observed in approximately 6,500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.6466dupA in the DSP gene is interpreted as a pathogenic variant.
Invitae	RCV000699748	SCV000828473	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2022-10-03	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with DSP-related conditions. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DSP protein in which other variant(s) (p.Arg2166*, p.Gly2414*, p.Ser2168Argfs*18) have been determined to be pathogenic (PMID: 23671136, 27532257; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 419496). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2156Lysfs*9) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 716 amino acid(s) of the DSP protein.
Ambry Genetics	RCV003168946	SCV003867563	pathogenic	Cardiovascular phenotype	2022-12-16	criteria provided, single submitter	clinical testing	The c.6466dupA pathogenic mutation, located in coding exon 24 of the DSP gene, results from a duplication of A at nucleotide position 6466, causing a translational frameshift with a predicted alternate stop codon (p.R2156Kfs*9). This alteration occurs at the 3' terminus of theDSP gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 716 amino acids (25%) of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Alterations in DSP that result in haploinsufficiency or protein truncation have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM) (Fressart V et al. Europace. 2010;12(6):861-8; Elliott P et al. Circ Cardiovasc Genet. 2010;3(4):314-22; Quarta G et al. Circulation. 2011;123(23):2701-9; Garcia-Pavia P et al. Heart. 2011;97(21):1744-52; Rasmussen TB et al. Clin Genet. 2013;84(1):20-30; Pugh TJ et al. Genet Med. 2014;16(8):601-8). This variant has been detected in an individual from an exome sequencing cohort without overt ARVC; however, a portion of individuals in this cohort exhibited some features of ARVC or DCM (Carruth ED et al. Circ Genom Precis Med. 2021 Apr;14(2):e003302). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.