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

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

DSP
NM_004415.4 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 0.770
Variant links:
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]

Genome browser will be placed here

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 6-7579995-C-T is Pathogenic according to our data. Variant chr6-7579995-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 199881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7579995-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DSPNM_004415.4 linkuse as main transcriptc.3805C>T p.Arg1269* stop_gained 23/24 ENST00000379802.8 NP_004406.2 P15924-1B4DKX6
DSPNM_001319034.2 linkuse as main transcriptc.3805C>T p.Arg1269* stop_gained 23/24 NP_001305963.1 P15924-3B4DKX6
DSPNM_001008844.3 linkuse as main transcriptc.3582+223C>T intron_variant NP_001008844.1 P15924-2B4DKX6Q4LE79

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DSPENST00000379802.8 linkuse as main transcriptc.3805C>T p.Arg1269* stop_gained 23/241 NM_004415.4 ENSP00000369129.3 P15924-1
DSPENST00000418664.2 linkuse as main transcriptc.3582+223C>T intron_variant 1 ENSP00000396591.2 P15924-2
DSPENST00000710359.1 linkuse as main transcriptc.3805C>T p.Arg1269* stop_gained 23/24 ENSP00000518230.1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152084
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250796
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135714
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461856
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000629
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152084
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74286
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

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:2
Pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthAug 08, 2023This 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 providedclinical testingBiochemical Molecular Genetic Laboratory, King Abdulaziz Medical CityFeb 05, 2020- -
Cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 11, 2023This 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 submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioNov 09, 2021- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 02, 2023Nonsense 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 submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsAug 24, 2021- -
Arrhythmogenic right ventricular dysplasia 8 Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineJan 09, 2018This 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 submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteJul 02, 2020Based 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 17, 2024This 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 submitterclinical testingAmbry GeneticsJan 26, 2023The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
36
DANN
Uncertain
1.0
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.81
D
Vest4
0.77
GERP RS
0.78
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs767643821; hg19: chr6-7580228; COSMIC: COSV65791758; API