chr6-7576986-C-T

Position:

• chr6-7576986-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.2821C>T​(p.Arg941Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,766 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: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DSP NM_004415.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.36

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 6-7576986-C-T is Pathogenic according to our data. Variant chr6-7576986-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7576986-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.2821C>T	p.Arg941Ter	stop_gained	20/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.2821C>T	p.Arg941Ter	stop_gained	20/24		NP_001305963.1
DSP	NM_001008844.3	c.2821C>T	p.Arg941Ter	stop_gained	20/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.2821C>T	p.Arg941Ter	stop_gained	20/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.2821C>T	p.Arg941Ter	stop_gained	20/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.2821C>T	p.Arg941Ter	stop_gained	20/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460766 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726628

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2017	p.Arg941Stop (CGA>TGA): c.2821 C>T in exon 20 of the DSP gene (NM_004415.2). The Arg941Stop nonsense mutation in the DSP gene has been reported previously in association with ARVC (Quarta G et al., 2011). This mutation is predicted to cause loss of normal protein function either due to production of an abnormal, prematurely truncated protein, or by absence of protein product due to nonsense mediated mRNA decay. Other nonsense mutations (Gln625Stop, Gln2667Stop) have been reported in the DSP gene associated with ARVC. Furthermore, Arg941Stop was not observed in 300 control individuals tested (Quarta G et al., 2011). Therefore, Arg941Stop in the DSP gene is interpreted as a disease-causing mutation. The variant is found in ARVC panel(s). -

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 21, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 180326). This premature translational stop signal has been observed in individual(s) with arrythmogenic right ventricular cardiomyopathy (PMID: 21606390). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg941*) 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). -

Cardiac arrest Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

Sep 04, 2014

- -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jul 19, 2018

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2022

The p.R941* pathogenic mutation (also known as c.2821C>T), located in coding exon 20 of the DSP gene, results from a C to T substitution at nucleotide position 2821. This changes the amino acid from an arginine to a stop codon within coding exon 20. This alteration has been reported in an individual with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) (Quarta G et al. Circulation, 2011 Jun;123:2701-9; Gomes J et al. Eur Heart J, 2012 Aug;33:1942-53; Bariani R et al. Europace, 2021 06;23:907-917). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial isolated arrhythmogenic right ventricular dysplasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Nov 14, 2016

Variant summary: The DSP c.2821C>T (p.Arg941X) variant results in a premature termination codon, predicted to cause a truncated or absent DSP protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If NMD is escaped, the variant is expected to truncate spectrin/alpha-actinin domain and plectin repeats in the protein (InterPro). Truncations downstream of this position have been classified as likely pathogenic by our laboratory (e.g. p.Arg1738X, c.6273delA, etc.). This variant is absent in 121116 control chromosomes, including large and broad populations from ExAC. In literature, this variant has been reported in two ARVD patients/families (Quarta_2011, Gomes_2012). Multiple clinical laboratories have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A;A
Vest4		0.88
GERP RS		5.8
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

Other links and lift over

dbSNP: rs730880082; hg19: chr6-7577219;