6-7579995-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_004415.4(DSP):c.3805C>T(p.Arg1269*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,940 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
Consequence
NM_004415.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.3805C>T | p.Arg1269* | stop_gained | 23/24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001319034.2 | c.3805C>T | p.Arg1269* | stop_gained | 23/24 | NP_001305963.1 | ||
DSP | NM_001008844.3 | c.3582+223C>T | intron_variant | NP_001008844.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.3805C>T | p.Arg1269* | stop_gained | 23/24 | 1 | NM_004415.4 | ENSP00000369129.3 | ||
DSP | ENST00000418664.2 | c.3582+223C>T | intron_variant | 1 | ENSP00000396591.2 | |||||
DSP | ENST00000710359.1 | c.3805C>T | p.Arg1269* | stop_gained | 23/24 | ENSP00000518230.1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250796Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135714
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461856Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727222
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74286
ClinVar
Submissions by phenotype
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 08, 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 has shown decreased variant transcript and protein expression in keratinocytes and endocardium biopsy samples from carriers, indicating potential haploinsufficiency through nonsense-mediated mRNA decay (PMID: 23137101). This variant has been reported in four individuals from a family affected with arrhythmogenic right ventricular cardiomyopathy, including 1 clinically symptomatic individual, 2 carriers with varying degrees of subclinical phenotype presentations, and 1 asymptomatic carrier (PMID: 23137101). This variant has been identified in 1/250796 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. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Feb 05, 2020 | - - |
Cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 11, 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 has shown decreased variant transcript and protein expression in keratinocytes and endocardium biopsy samples from carriers, indicating potential haploinsufficiency through nonsense-mediated mRNA decay (PMID: 23137101). This variant has been reported in four individuals from a family affected with arrhythmogenic right ventricular cardiomyopathy, including 1 clinically symptomatic individual, 2 carriers with varying degrees of subclinical phenotype presentations, and 1 asymptomatic carrier (PMID: 23137101). This variant has been identified in 1/250796 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 09, 2021 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 02, 2023 | 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: 26383259, 28436997, 31447099, Glazer2021[preprint], 31402444, 34515413, 23137101) - |
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Aug 24, 2021 | - - |
Arrhythmogenic right ventricular dysplasia 8 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Jan 09, 2018 | This c.3805C>T variant in the DSP gene is predicted to introduce a premature translation termination codon. It has been reported in three individuals in a family with arrhythmogenic right ventricular cardiomyopathy (ARVC; PMID 23137101). Functional analysis in endomyocardial biopsies of the proband indicates that the mutant transcript is likely to be degraded through nonsense-mediated decay and that DSP protein expression levels are decreased (PMID 23137101). This c.3805C>T, p.Arg1269* variant in the DSP gene is classified as likely pathogenic - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 02, 2020 | Based on the classification scheme VCGS_Germline_v1.3.3, 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 ARVC. (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete (age-dependent) penetrance and variable expressivity is a well-described aspect of arrhythmogenic cardiomyopathy (PMID: 29062697). (I) 0115 - Variants in this gene are known to have variable expressivity. (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) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported (ClinVar, PMID: 23137101 - in three members of a family with syncope/sustained VT/right ventricular wall aneurysm, PMID: 26383259 - case of sudden cardiac death with features of hypertrophy and fibro-fatty infiltrations). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
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 | Jan 17, 2024 | This sequence change creates a premature translational stop signal (p.Arg1269*) 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 present in population databases (rs767643821, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 23137101). ClinVar contains an entry for this variant (Variation ID: 199881). For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2023 | The p.R1269* pathogenic mutation (also known as c.3805C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 3805. This changes the amino acid from an arginine to a stop codon within coding exon 23. This alteration has been reported in a family with features of arrhythmogenic right ventricular cardiomyopathy (ARVC) (Rasmussen TB et al. Clin Genet, 2013 Jul;84:20-30). This alteration has also been reported in sudden cardiac death and dilated cardiomyopathy (DCM) cohorts (Hertz CL et al. Int J Legal Med, 2016 Jan;130:91-102; Janin A et al. Clin Genet, 2017 Dec;92:616-623). 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 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at