Submissions for variant NM_004415.4(DSP):c.939+1G>A (rs727504443)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000211717	SCV000204706	likely pathogenic	Primary dilated cardiomyopathy; Arrhythmogenic right ventricular cardiomyopathy	2015-01-05	criteria provided, single submitter	clinical testing	The c.939+1G>A variant in DSP has been reported in 2 individuals with ARVC, 1 wi th LDAC and 1 with palmoplantar hyperkeratosis (unknown cardiac status) (Whittoc k 1999, Sen Chowdry 2008, Christensen 2010, Asimaki 2009-refered to as 1218+1G>A ). This variant has been identified by our laboratory in 1 individual with DCM a nd segregated with disease in 1 affected relative. It was absent from large popu lation studies. This variant occurs in the invariant region (+/- 1,2) of the spl ice consensus sequence and studies have shown that it alters splicing, leading t o retention of intron 7 and a premature termination codon (Whittock 1999). Splic e site and other loss of function variants in DSP have been reported in patients with ARVC (http://arvcdatabase.info/). In summary, although additional studies are required to fully establish its clinical significance, the c.939+1G>A varian t is likely pathogenic.
Invitae	RCV000791442	SCV000288554	pathogenic	Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8	2018-09-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7. It disrupts mRNA splicing and results in an absent or disrupted protein product. Truncating variants in DSP are known to be pathogenic. This particular truncation has been reported in the literature in patients with palmoplantar keratoderma, left dominant arrhythmogenic cardiomyopathy, arrhythmogenic right ventricular dysplasia, and dilated cardiomyopathy  (PMID: 10594734, 19095136, 20864495, 24503780). ClinVar contains an entry for this variant (Variation ID: 178282). Experimental studies have shown that this splice donor change leads to aberrant splicing leading to the retention of intron 7, which contains a premature termination codon within the N-terminal domain of the peptide (PMID: 10594734). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000421912	SCV000520843	pathogenic	not provided	2018-02-21	criteria provided, single submitter	clinical testing	The c.939+1 G>A variant in the DSP gene was initially described in a case of autosomal dominant striatepalmoplantar keratoderma and was reported to segregate with disease in an affected mother and child. However, therewas no mention of a cardiomyopathy phenotype in these individuals (Whittock et al., 1999). Subsequently, c.939+1G>A has been reported in cases of left-dominant arrhythmogenic cardiomyopathy, ARVC, and DCM (Sen-Chowdhryet al., 2008; Christensen et al.,2010; Pugh et al., 2014). Furthermore, the c.939+1 G>A variant was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. The c.939+1 G>A variant occurs at anucleotide position that is conserved across species. Moreover, in the same study by Whittock et al. (1999), PCRanalysis on patient cDNA and genomic DNA demonstrated that c.939+1 G>A results in the inclusion of all of intron7 into the variant mRNA, leading to a downstream premature termination codon. Finally, other splice site variantshave been reported in the DSP gene in HGMD in association with ARVC and DCM (Stenson et al., 2014), thereforeshowing that truncation is a known disease mechanism.In summary, c.939+1 G>A in the DSP gene is interpreted as a pathogenic variant.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute	RCV000845383	SCV000987442	pathogenic	Arrhythmogenic right ventricular cardiomyopathy		criteria provided, single submitter	clinical testing
OMIM	RCV000656500	SCV000778498	pathogenic	Keratosis palmoplantaris striata II	2010-11-01	no assertion criteria provided	literature only
OMIM	RCV000155023	SCV000778499	pathogenic	Arrhythmogenic right ventricular cardiomyopathy, type 8	2010-11-01	no assertion criteria provided	literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000421912	SCV000924774	likely pathogenic	not provided	2016-11-02	no assertion criteria provided	provider interpretation	c.939+1G>A in DSP (NM_004415.2) Seen in a family with familial DCM. Testing done at Invitae. Given that this type of variation is typically pathogenic in this gene, the supporting experimental data, case data, and rarity, we consider this variant likely pathogenic and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Given that splice variants are known to be pathogenic in DSP and this specific variant has in vitro evidence for aberrant splicing, we did not do a thorough independent review of the data on the variant. Per the lab report, the variant "as been reported in the literature in patients with palmoplantar keratoderma, left dominant arrhythmogenic cardiomyopathy, arrhythmogenic right ventricular dysplasia, and dilated cardiomyopathy (PMID: 10594734, 19095136, 20864495, 24503780)." There is no variation at this nucleotide listed in the ExAC, which currently includes variant calls on >60,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in ExAC is >50x.