6-7579323-C-T

Position:

• chr6-7579323-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004415.4(DSP):​c.3133C>T​(p.Arg1045*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000342 in 1,461,860 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: 0.0000034 (0 hom.)
• Consequence: DSP NM_004415.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.38

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]

ACMG classification

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 6-7579323-C-T is Pathogenic according to our data. Variant chr6-7579323-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 464961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7579323-C-T is described in Lovd as [Likely_pathogenic]. Variant chr6-7579323-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.3133C>T	p.Arg1045*	stop_gained	23/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.3133C>T	p.Arg1045*	stop_gained	23/24		NP_001305963.1
DSP	NM_001008844.3	c.3133C>T	p.Arg1045*	stop_gained	23/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.3133C>T	p.Arg1045*	stop_gained	23/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.3133C>T	p.Arg1045*	stop_gained	23/24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.3133C>T	p.Arg1045*	stop_gained	23/24			ENSP00000518230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

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

Jun 23, 2017

The p.Arg1045X variant in DSP has not been previously reported in individuals wi th cardiomyopathy or in large population studies. This nonsense variant leads to a premature termination codon at position 1045, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the DSP gene is a n established disease mechanism in individuals with arrhythmogenic right ventric ular cardiomyopathy, and has recently been associated with dilated cardiomyopath y. In summary, although additional studies are required to fully establish its c linical significance, the p.Arg1045X variant is likely 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

Nov 05, 2023

This sequence change creates a premature translational stop signal (p.Arg1045*) 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 or arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257, 28527814). ClinVar contains an entry for this variant (Variation ID: 464961). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jul 09, 2021

PVS1, PM2_supporting; PS4_moderate -

Primary dilated cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Nov 03, 2022

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2023

The p.R1045* pathogenic mutation (also known as c.3133C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 3133. This changes the amino acid from an arginine to a stop codon within coding exon 23. This alteration has been reported in one individual from a dilated cardiomyopathy (DCM) genetic testing cohort and in one individual with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Walsh R et al. Genet. Med., 2017 02;19:192-203; Castelletti S et al. Int. J. Cardiol., 2017 Dec;249:268-273). 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 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. -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 05, 2023

Variant summary: DSP c.3133C>T (p.Arg1045X) 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. A truncation downstream of this position has been classified as pathogenic by our laboratory (c.3337C>T, p.Arg1113X). The variant was absent in 250892 control chromosomes (gnomAD). The variant, c.3133C>T, has been reported in the literature in individuals affected with dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy (Walsh_2017, Castelletti_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27532257, 28527814). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic or likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.97	D
Vest4		0.84
GERP RS		3.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6

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

Other links and lift over

dbSNP: rs1554108012; hg19: chr6-7579556;