6-7579989-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004415.4(DSP):c.3799C>T(p.Arg1267*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,844 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: 0.0000014 ( 0 hom. )
Consequence
DSP
NM_004415.4 stop_gained
NM_004415.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 2.61
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 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-7579989-C-T is Pathogenic according to our data. Variant chr6-7579989-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7579989-C-T is described in Lovd as [Likely_pathogenic]. Variant chr6-7579989-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.3799C>T | p.Arg1267* | stop_gained | 23/24 | ENST00000379802.8 | NP_004406.2 | |
| DSP | NM_001319034.2 | c.3799C>T | p.Arg1267* | stop_gained | 23/24 | NP_001305963.1 | ||
| DSP | NM_001008844.3 | c.3582+217C>T | intron_variant | NP_001008844.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DSP | ENST00000379802.8 | c.3799C>T | p.Arg1267* | stop_gained | 23/24 | 1 | NM_004415.4 | ENSP00000369129.3 | ||
| DSP | ENST00000418664.2 | c.3582+217C>T | intron_variant | 1 | ENSP00000396591.2 | |||||
| DSP | ENST00000710359.1 | c.3799C>T | p.Arg1267* | stop_gained | 23/24 | ENSP00000518230.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461844Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727222
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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
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:3
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2006 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 02, 2023 | This variant changes 1 nucleotide in exon 23 of the DSP gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A study with skin biopsies from carrier individuals has shown that this variant causes an absent expression of the major DSP transcript (NM_004415) in the heart (PMID: 16467215). This variant has been reported in homozygous state in an individual affected with arrhythmogenic cardiomyopathy with epidermolytic palmoplantar keratoderma and wooly hair (PMID: 16467215), and in compound heterozygous state with another DSP pathogenic variant in an individual affected with arrhythmogenic-dilated cardiomyopathy with epidermolytic palmoplantar keratoderma and wooly hair (PMID: 30993396). This variant has also been reported in compound heterozygous state with a DSP variant of uncertain significance in two twin brothers affected with early-onset dilated cardiomyopathy (PMID: 30398466), and in heterozygous state in an individual suspected of having hereditary cardiomyopathy (PMID: 35083019) as well as in five asymptomatic individuals (PMID: 16467215, 30398466, 30993396). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 10, 2024 | Variant summary: DSP c.3799C>T (p.Arg1267X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250804 control chromosomes. c.3799C>T has been reported in the literature in individuals affected with Carvajal Syndrome and dilated Cardiomyopathy (Uzumcu_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 16467215). ClinVar contains an entry for this variant (Variation ID: 16845). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 10, 2022 | Reported in the heterozygous state in association with DCM and arrhythmogenic cardiomyopathy; however, patient-specific details were not provided (Marschall et al., 2019; Reza et al., 2022); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 16467215, 34426522, 30398466, 31737537, 30993396, 31073624, 34691145, 35083019) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
Primary dilated cardiomyopathy;C0023976:Long QT syndrome Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Blueprint Genetics | Jul 10, 2014 | - - |
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 | Jun 20, 2023 | ClinVar contains an entry for this variant (Variation ID: 16845). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individuals with clinical features of Carvajal syndrome (PMID: 16467215, 30993396). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1267*) 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). - |
Cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 21, 2023 | This variant changes 1 nucleotide in exon 23 of the DSP gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A study with skin biopsies from carrier individuals has shown that this variant causes an absent expression of the major DSP transcript (NM_004415) in the heart (PMID: 16467215). This variant has been reported in homozygous state in an individual affected with arrhythmogenic cardiomyopathy with epidermolytic palmoplantar keratoderma and wooly hair (PMID: 16467215), and in compound heterozygous state with another DSP pathogenic variant in an individual affected with arrhythmogenic-dilated cardiomyopathy with epidermolytic palmoplantar keratoderma and wooly hair (PMID: 30993396). This variant has also been reported in compound heterozygous state with a DSP variant of uncertain significance in two twin brothers affected with early-onset dilated cardiomyopathy (PMID: 30398466), and in heterozygous state in an individual suspected of having hereditary cardiomyopathy (PMID: 35083019) as well as in five asymptomatic individuals (PMID: 16467215, 30398466, 30993396). 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. - |
Primary dilated cardiomyopathy Pathogenic:1
| 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 DSP-related cardiac disorders including arrhythmogenic right ventricular dysplasia 8 (MIM#607450) and dilated cardiomyopathy (MONDO#0005021), 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 (preprint by Hoorntje, E.T. et al. (2021)). (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) 0702 - Other premature termination variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (ClinVar). At least nine comparable NMD-predicted variants have been reported in individuals with sudden death or DSP-related cardiac conditions (VCGS, ClinVar, PMIDs: 26383259, 27532257, 29915097). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic/pathogenic by multiple clinical testing laboratories (ClinVar). It has also been reported in individuals with DSP-related cardiac conditions (PMIDs: 35083019, 30398466, 30993396). In addition, it has been reported in asymptomatic family members (PMIDs: 30398466, 30993396). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 23, 2023 | The p.R1267* pathogenic mutation (also known as c.3799C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 3799. This changes the amino acid from an arginine 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 particular variant has been reported in the homozygous state in a subject with left and right ventricular involvement, wooly hair and palmar keratoderma (Uzumcu A et al. J. Med. Genet., 2006 Feb;43:e5). This variant has also been reported in the compound heterozygous state in two siblings with dilated cardiomyopathy (DCM) (Surmacz R et al. Pol. Arch. Intern. Med., 2018 12;128:785-787). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. Based on the supporting evidence, 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
Pathogenic
Eigen_PC
Pathogenic
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