Submissions for variant NM_004415.4(DSP):c.4822C>T (p.Gln1608Ter)

dbSNP: rs1060500610

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001388391	SCV001589358	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1608*) 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 clinical features of DSP-related conditions (PMID: 32372669). ClinVar contains an entry for this variant (Variation ID: 405234). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002339123	SCV002635056	pathogenic	Cardiovascular phenotype	2018-10-30	criteria provided, single submitter	clinical testing	The p.Q1608* pathogenic mutation (also known as c.4822C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 4822. This changes the amino acid from a glutamine to a stop codon within coding exon 23. 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 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786116	SCV000924776	likely pathogenic	not provided	2017-05-17	no assertion criteria provided	provider interpretation	p.Gln1608* (c.4822C>T) in exon 23 of the DSP gene (NM_004415.2) Given that this is a truncating variant in a gene in which haploinsufficiency is a known mechanism of disease, and its association with both arrhythmogenic right ventricular cardiomyopathy (ARVC) and non-ischemic dilated cardiomyopathy (DCM), we consider this variant likely disease-causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). DSP is associated with both ARVC and DCM. This is a novel variant and does not have an entry in ClinVar. However, the majority of the mutations in the DSP gene associated with ARVC and DCM are nonsense or frameshift mutations (Stenson P et al., 2009). haploinsufficiency is a known mechanism of disease (Yang et al 2006). Furthermore, in the ExAC constraint analyses indicates DSP is intolerant to loss of function/truncating variation (pLI - 1.000) and cardiodb.org lists truncating variants in DSP enriched both cases of ARVC and DCM vs. controls. Walsh et al (2016) found that truncating DSP variants were enriched in cases of DCM over ExAC controls with odds ration of 41.0. The c-terminal end of the protein, which is altered by this frameshift, is important for protein interactions with IFs to anchor them to the desmosome (Kouklis et al. 1994; Bornslaeger et al. 1996). Groeneweg et al. (2016) reports on 1001 ARVC index patients from the Hopkins cohort. Nine of eleven index patients have either nonsense or frameshift variants in the DSP gene. Sen-Chowdry et a. (2007) noted that 68 of their 200 patients presenting to ARVC clinic had left ventricular wall abnormalities, with septal hypokinesia the most common. Although the heart function was abnormal, there was no evidence for involvement of ARVC in the LV. 68 of these patients had LV dilation and 31 had a reduced LVEF. Lopez-Ayala et al. (2014) reported on the outcome of sequencing DSP in 47 patients with either DCM or ARVC who presented with either arrhythmia or sudden cardiac arrest/death. Three of these probands were found to have the same truncating variant in DSP (c.1339C>T - not our patients' familial variant). 15 relatives were found to be carriers after cascade genetic screening. The first symptoms were: sustained VT in 6 carriers and left ventricular impairment in 9. MRI noted LV involvement in 9 cases and biventricular disease in 3. Fibrosis was seen in 6 family members and non-compaction in 5. In the first family, the 37 years old proband presented with an episode of sustained VT at rest. An echocardiogram showed LV dilation and systolic dysfunction. His mother was diagnosed with idiopathic DCM at 67 years old after ruling out coronary artery disease. The maternal grandfather died in his sleep at 37 years old after suffering from heart failure. Other family members, including 2 siblings, have since developed symptoms. The two siblings had progressive systolic dysfunction. In the second family, the 42 years old proband presented with a pre-syncopal episode of sustained VT and echocardiogram noted global LV hypokinesia and moderately impaired systolic dysfunction. Her 72 years old mother's echocardiogram showed severe systolic impairment without CAD. A maternal aunt died suddenly at 40 years old. The third family's proband, a 62 years old woman, presented with acute heart failure and an echocardiogram showed moderately impaired systolic function and MRI results led to the diagnosis of LVNC. Her daughter had "myocarditis" at 32 years old and his 45 year old nephew presented with cardiac arrest while walking. His nephew was diagnosed with LVNC and moderate systolic dysfunction. The glutamine at codon 1608 is moderately conserved across species, as are neighboring amino acids. This variant is not present in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 urelated individuals of African, Asian, European, Latino, and Ashkenazi descent. There is no variation present at codon 1608 in gnomAD. The average coverage at that site in gnomAD is ~84x for exomes and ~34x for genomes.