Submissions for variant NM_004415.4(DSP):c.928dup (p.Glu310fs)

dbSNP: rs794728137

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181358	SCV000233659	pathogenic	not provided	2017-08-11	criteria provided, single submitter	clinical testing	The c.928dupG pathogenic variant in the DSP gene has previously been reported in one pediatric patient with sudden cardiac arrest/death (Li et al., 2015); however no additional clinical or segregation data was provided. In addition, it has been observed to segregate with a DCM phenotype in at least one affected relative from a family tested at GeneDx. This variant causes a shift in reading frame starting at codon Glutamic Acid 310, changing it to a Glycine, and creating a premature stop codon at position 13 of the new reading frame, denoted p.Glu310GlyfsX13. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multiple other downstream frameshift variants in the DSP gene have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014). Furthermore, the c.928dupG variant 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.In summary, c.928dupG in the DSP gene is interpreted as a pathogenic variant.
Invitae	RCV000559042	SCV000639748	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu310Glyfs*13) in the DSP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 26187847, 28527814). ClinVar contains an entry for this variant (Variation ID: 199916). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002372109	SCV002686664	pathogenic	Cardiovascular phenotype	2021-05-26	criteria provided, single submitter	clinical testing	The c.928dupG pathogenic mutation, located in coding exon 7 of the DSP gene, results from a duplication of G at nucleotide position 928, causing a translational frameshift with a predicted alternate stop codon (p.E310Gfs*13). In general, 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 alteration has been reported in an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort and a pediatric sudden cardiac arrest/death cohort (Li MH et al. Hum Genomics, 2015 Jul;9:15; Castelletti S et al. Int J Cardiol, 2017 Dec;249:268-273). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477886	SCV000536704	likely pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Lethal acantholytic epidermolysis bullosa; Woolly hair-skin fragility syndrome; Keratosis palmoplantaris striata 2; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis	2014-11-06	no assertion criteria provided	research