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

gnomAD frequency: 0.00001  dbSNP: rs727504443

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791442	SCV000288554	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7 of the DSP gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs727504443, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with arrhythmogenic right ventricular dysplasia, dilated cardiomyopathy, left dominant arrhythmogenic cardiomyopathy, and/or palmoplantar keratoderma (PMID: 10594734, 19095136, 20864495, 24503780). ClinVar contains an entry for this variant (Variation ID: 178282). Studies have shown that disruption of this splice site results in the retention of intron 7, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 10594734). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000421912	SCV000520843	pathogenic	not provided	2023-01-05	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing; Published functional studies demonstrate aberrant splicing leading to retention of the entire intron 7, which contains a premature termination codon within the N-terminal domain of the peptide (Whittock et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20738328, 25163546, 19095136, 24503780, 27532257, 10594734, 31317183, 32372669, 31402444, 31447099, 34352074, 30847666, 34135346, 20864495)
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV002372015	SCV000987442	pathogenic	Cardiovascular phenotype	2022-02-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002372015	SCV002686397	pathogenic	Cardiovascular phenotype	2023-11-15	criteria provided, single submitter	clinical testing	The c.939+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 7 of the DSP gene. This mutation was identified in a family with striate palmoplantar keratoderma; six individuals were heterozygous with 3 symptomatic. This mutation was identified in individuals with dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy; some individuals also had variants in other cardiac-related genes (Sen-Chowdhry S et al. J. Am. Coll. Cardiol., 2008 Dec;52:2175-87; Christensen AH et al. J. Med. Genet., 2010 Nov;47:736-44; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Haas J et al. Eur. Heart J., 2015 May;36:1123-35a; Walsh R et al. Genet. Med., 2017 02;19:192-203). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. In addition, RNA studies have suggested that this variant results in aberrant splicing and nonsense-mediated decay (Whittock NV et al. J. Invest. Dermatol., 1999 Dec;113:940-6). 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486698	SCV004240548	pathogenic	Cardiomyopathy	2022-08-02	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000155023	SCV005399834	pathogenic	Arrhythmogenic right ventricular dysplasia 8	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with arrhythmogenic right ventricular dysplasia 8 (MIM#607450) and other DSP-related cardiac disorders. (I) 0108 - This gene is associated with both recessive and dominant disease. Variants in this gene are usually inherited in a dominant manner, however rare reports of recessive inheritance have resulted in a more severe cardiac phenotype (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. In families with cardiomyopathies, reduced penetrance has been reported among family members aged 60-86 years (PMID: 36580316). (I) 0115 - Variants in this gene are known to have variable expressivity. Age-dependent penetrance and variable expressivity are well-described aspects of arrhythmogenic cardiomyopathy (PMID: 29062697). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Nested PCR of patient cDNA described the inclusion of intron 7 and a new stop codon twenty-five amino acids downstream. This new protein product would be predicted to undergo nonsense-mediated decay; however the relevant data was not shown by the authors and this information was interpreted with caution (PMID: 10594734). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0703 - Other splice site variants comparable to the one identified in this case has moderate previous evidence for pathogenicity. Two variants (c.939+1G>T, c.939+2T>C) at this canonical splice site have been reported once each as pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported seven times as pathogenic and once as likely pathogenic (ClinVar). It has also been reported in an individual with arrhythmogenic right ventricular cardiomyopathy (PMID: 20864495), an individual with left-dominant arrhythmogenic cardiomyopathy (PMID: 19095136) and in a family with striate palmoplantar keratoderma with no mention of cardiac status (PMID: 10594734). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
All of Us Research Program, National Institutes of Health	RCV004806092	SCV005428806	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-06-27	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 7 of the DSP gene. A functional RNA study with a skin biopsy from a patient has shown that this variant causes the retention of intron 7, resulting in premature termination codon 25 amino acids downstream from the splice site. Only low levels of the mutant transcript were detected, indicating the variant leads to transcript degradation via nonsense-mediated mRNA decay (PMID: 10594734). This variant has been reported in an individual affected with striate palmoplantar keratoderma, and has been observed to segregate with disease in two relatives from the family (PMID: 10594734). This individual was later reported to be also affected with left-dominant arrhythmogenic cardiomyopathy (PMID: 19095136). Additionally, this variant has been identified in four other individuals with arrhythmogenic cardiomyopathy (PMIDs: 20864495, 36431211), at least three individuals with dilated cardiomyopathy (PMIDs: 24503780, 27532257; ClinVar SCV000924774.1, SCV000204706.4), an individual suspected of having hereditary cardiomyopathies (PMID: 35083019), an asymptomatic individual with a family history of arrhythmogenic cardiomyopathy (PMID: 36138163), and a healthy individual aged 70 years or older with no history of coronary heart disease (PMID: 34135346). This variant has been identified in 1/31370 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV003486698	SCV006064780	pathogenic	Cardiomyopathy	2024-04-22	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 7 of the DSP gene. A functional RNA study with a skin biopsy from a patient has shown that this variant causes the retention of intron 7, resulting in premature termination codon 25 amino acids downstream from the splice site. Only low levels of the mutant transcript were detected, indicating the variant leads to transcript degradation via nonsense-mediated mRNA decay (PMID: 10594734). This variant has been reported in an individual affected with striate palmoplantar keratoderma, and has been observed to segregate with disease in two relatives from the family (PMID: 10594734). This individual was later reported to be also affected with left-dominant arrhythmogenic cardiomyopathy (PMID: 19095136). Additionally, this variant has been identified in four other individuals with arrhythmogenic cardiomyopathy (PMIDs: 20864495, 36431211), at least three individuals with dilated cardiomyopathy (PMIDs: 24503780, 27532257; ClinVar SCV000924774.1, SCV000204706.4), an individual suspected of having hereditary cardiomyopathies (PMID: 35083019), an asymptomatic individual with a family history of arrhythmogenic cardiomyopathy (PMID: 36138163), and a healthy individual aged 70 years or older with no history of coronary heart disease (PMID: 34135346). This variant has been identified in 1/31370 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
OMIM	RCV000656500	SCV000778498	pathogenic	Keratosis palmoplantaris striata 2	2010-11-01	no assertion criteria provided	literature only
OMIM	RCV000155023	SCV000778499	pathogenic	Arrhythmogenic right ventricular dysplasia 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000421912	SCV001742278	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000421912	SCV001917160	pathogenic	not provided		no assertion criteria provided	clinical testing