6-7559281-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_004415.4(DSP):c.478C>T(p.Arg160*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
DSP
NM_004415.4 stop_gained
NM_004415.4 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 2.79
Genes affected
DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 6-7559281-C-T is Pathogenic according to our data. Variant chr6-7559281-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7559281-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DSP | NM_004415.4 | c.478C>T | p.Arg160* | stop_gained | 4/24 | ENST00000379802.8 | NP_004406.2 | |
| DSP | NM_001319034.2 | c.478C>T | p.Arg160* | stop_gained | 4/24 | NP_001305963.1 | ||
| DSP | NM_001008844.3 | c.478C>T | p.Arg160* | stop_gained | 4/24 | NP_001008844.1 | ||
| DSP | NM_001406591.1 | c.478C>T | p.Arg160* | stop_gained | 4/11 | NP_001393520.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DSP | ENST00000379802.8 | c.478C>T | p.Arg160* | stop_gained | 4/24 | 1 | NM_004415.4 | ENSP00000369129.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461712Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727140
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31
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2
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727140
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 07, 2022 | PM2_supporting, PS4, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 03, 2024 | Identified in individuals referred for genetic testing at GeneDx and in published literature with features of desmoplakin cardiomyopathy, including ACM and DCM, with and without additional features of curly hair and/or palmoplantar keratoderma (PMID: 23810894, 25820315, 31319917, 31317183, 31386562, 33079602, 32372669, 34352074); Reported in a patient with arrhythmogenic cardiomyopathy, sudden cardiac arrest due to ventricular fibrillation, and cutaneous abnormalities; this variant segregated with a cutaneous phenotype in relatives, including a sibling with palmoplantar keratoderma in the absence of cardiac dysfunction (PMID: 35151254); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26850880, 25820315, 27532257, 28471438, 28588093, 36264615, 36580316, 37652022, 38169814, 36129056, 23810894, 31402444, Lee2023[CaseReport], 35054841, 31317183, 31386562, 29997227, 34352074, 35083019, 32372669, 33079602, 31319917, 35151254, 29633331) - |
| Pathogenic, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Dec 09, 2016 | Given that it is a nonsense variant in a gene where loss of function is a known mechanisms of disease, absence in control populations and moderate case data, we consider this variant likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 2 unrelated case of arrhythmogenic right ventricular cardiomyopathy (ARVC) (not including this patient's family). The number of cases may be more, but it is difficult to discern because the patient reported below may have had testing at either GeneDx or LMM, and may be redundant with the ClinVar entries. This variant has an entry in ClinVar. GeneDx asserts that it is pathogenic and LMM asserts that it is likely pathogenic. te Riele et al 2013 report this variant in a study reporting on value of cardiac MRI in risk stratification for patients with ARVC. The patients were recruited from the Johns Hopkins ARVC registry. They were eligible for the study if they had a pathogenic desmosomal variant and had no history of sustained VT or VF. No other specific phenotypic information was given. The majority of the mutations in the DSP gene associated with ARVC in HGMD are nonsense or frameshifts mutations (Stenson P et al., 2009). Furthermore, in the ExAC constraint analyses indicates DSP is intolerant to loss of function/truncating variation (pLI - 1.000). This variant is not listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >126,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 90x. It is also absent in the ExAC database. - |
Cardiomyopathy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | 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 cardiomyopathy (MONDO:0004994), DSP-related. (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) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as pathogenic/likely pathogenic (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in many individuals with DSP-related cardiac disorders and cutaneous symptoms (ClinVar, Cardio db, PMID:35151254, PMID:33079602, PMID:26850880, PMID:31319917). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 27, 2023 | This variant changes 1 nucleotide in exon 4 of the DSP gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with arrhythmogenic cardiomyopathy, dilated cardiomyopathy, and/or palmoplantar keratoderma (PMID: 25616645, 27532257, 28588093, 31317183, 31319917, 33079602, 35151254, 34352074). This variant has not been identified 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. - |
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This variant changes 1 nucleotide in exon 4 of the DSP gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with arrhythmogenic cardiomyopathy, dilated cardiomyopathy, and/or palmoplantar keratoderma (PMID: 25616645, 27532257, 28588093, 31317183, 31319917, 33079602, 35151254, 34352074). This variant has not been identified 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. - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 15, 2023 | This sequence change creates a premature translational stop signal (p.Arg160*) 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: 23810894). ClinVar contains an entry for this variant (Variation ID: 44922). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 17, 2016 | The p.Arg160X variant in DSP has been reported in 1 heterozygote with ARVC and 2 heterozygotes with ARVC/DCM, woolly hair, and palmoplantar keratoderma (Te Riel e 2013, LMM Data). It segregated with arrhythmia in one relative, and with wooll y hair and palmoplantar keratoderma in another relative from the same family. It was absent from large population studies. This nonsense variant leads to a prem ature termination codon at position 160, which is predicted to lead to a truncat ed or absent protein. Frameshift and nonsense variants in DSP have been reported in patients with ARVC (http://arvcdatabase.info/), but recent evidence supports that they can also cause DCM (Pugh 2014). When inherited in a recessive manner, multiple variants in DSP can result in ARVC or DCM with woolly hair and keratod erma or other skin findings (Norgett 2000, Alcalai 2003). In summary, although a dditional studies are required to fully establish its clinical significance, the p.Arg160X variant is likely pathogenic. - |
Primary dilated cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Feb 28, 2018 | This DSP Arg160Ter variant has been reported in 2 ARVC (te Riele et al., 2013, Walsh et al., 2017) and 1 DCM patient (Walsh et al., 2017). This variant is rare and is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified this variant in one DCM proband with a family history of disease and SCD. This variant was found to segregate to a sibling that died suddenly. Further, it has been found that nonsense mutations in DSP can lead to haploinsufficiency (Yang et al., 2006). In summary, because loss of function variants in DSP are a known mechanism of disease, the variant has been identified in several other affected probands and segregates to affected family members we classify DSP Arg160Ter as pathogenic. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 31, 2023 | The p.R160* pathogenic mutation (also known as c.478C>T), located in coding exon 4 of the DSP gene, results from a C to T substitution at nucleotide position 478. This changes the amino acid from an arginine to a stop codon within coding exon 4. This alteration has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM) patients (te Riele AS et al. J. Am. Coll. Cardiol., 2013 Nov;62:1761-9; Asimaki A et al. Circ Arrhythm Electrophysiol, 2016 Feb;9:e003688; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations in DSP that result in haploinsufficiency or protein truncation have been reported in additional patients with ARVC and 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. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at