rs727503001
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000379802.8(DSP):c.3630T>A(p.Tyr1210Ter) 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 1,461,866 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
ENST00000379802.8 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.3630T>A | p.Tyr1210Ter | stop_gained | 23/24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001319034.2 | c.3630T>A | p.Tyr1210Ter | stop_gained | 23/24 | NP_001305963.1 | ||
DSP | NM_001008844.3 | c.3582+48T>A | intron_variant | NP_001008844.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.3630T>A | p.Tyr1210Ter | stop_gained | 23/24 | 1 | NM_004415.4 | ENSP00000369129 | P2 | |
DSP | ENST00000418664.2 | c.3582+48T>A | intron_variant | 1 | ENSP00000396591 | A2 | ||||
DSP | ENST00000710359.1 | c.3630T>A | p.Tyr1210Ter | stop_gained | 23/24 | ENSP00000518230 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727228
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Primary dilated cardiomyopathy;C0349788:Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 16, 2013 | The Tyr1210X variant in DSP has not been reported in individuals with cardiomyop athy or in large population studies. This nonsense variant leads to a premature termination codon at position 1210, which is predicted to lead to a truncated or absent protein. Frameshift and nonsense variants in DSP have been reported in p atients with ARVC (http://arvcdatabase.info/) and DCM (Elliott 2010, Garcia-Pavi a 2011). In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance. - |
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 | Jul 14, 2023 | For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Tyr1210*) 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 dilated cardiomyopathy and/or epidermolysis bullosa (PMID: 29633331, 31737537, 32372669). ClinVar contains an entry for this variant (Variation ID: 163265). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 12, 2024 | Identified in individuals with features of desmoplakin cardiomyopathy referred for genetic testing at GeneDx and in published literature (PMID: 31737537, 32372669); 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: 32372669, 31737537, 29633331) - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 24, 2023 | The p.Y1210* pathogenic mutation (also known as c.3630T>A), located in coding exon 23 of the DSP gene, results from a T to A substitution at nucleotide position 3630. This changes the amino acid from a tyrosine to a stop codon within coding exon 23. This alteration has been reported in subjects with dilated cardiomyopathy (DCM) and has been reported in an exome sequencing cohort (Haggerty CM et al. Genet Med, 2017 Nov;19:1245-1252; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Ambry internal data). This alteration has also been reported as a compound heterozygote in a child with skin erosions, alopecia, nail dystrophy, follicular hyperkeratosis and palmoplantar keratoderma (Bari O et al. Pediatr Dermatol, 2018 Jul;35:e218-e220). 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at