6-7579989-C-T

Position:

• chr6-7579989-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.3799C>T​(p.Arg1267Ter) 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 1,461,844 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1267R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSP NM_004415.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.61

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 6-7579989-C-T is Pathogenic according to our data. Variant chr6-7579989-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7579989-C-T is described in Lovd as [Likely_pathogenic]. Variant chr6-7579989-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.3799C>T	p.Arg1267Ter	stop_gained	23/24	ENST00000379802.8
DSP	NM_001319034.2	c.3799C>T	p.Arg1267Ter	stop_gained	23/24
DSP	NM_001008844.3	c.3582+217C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.3799C>T	p.Arg1267Ter	stop_gained	23/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.3582+217C>T		intron_variant		1		A2
DSP	ENST00000710359.1	c.3799C>T	p.Arg1267Ter	stop_gained	23/24			A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461844 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 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 with skin biopsies from carrier individuals has shown that this variant causes an absent expression of the major DSP transcript (NM_004415) in the heart (PMID: 16467215). This variant has been reported in homozygous state in an individual affected with arrhythmogenic cardiomyopathy with epidermolytic palmoplantar keratoderma and wooly hair (PMID: 16467215), and in compound heterozygous state with another DSP pathogenic variant in an individual affected with arrhythmogenic-dilated cardiomyopathy with epidermolytic palmoplantar keratoderma and wooly hair (PMID: 30993396). This variant has also been reported in compound heterozygous state with a DSP variant of uncertain significance in two twin brothers affected with early-onset dilated cardiomyopathy (PMID: 30398466), and in heterozygous state in an individual suspected of having hereditary cardiomyopathy (PMID: 35083019) as well as in five asymptomatic individuals (PMID: 16467215, 30398466, 30993396). This variant has not been identified 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. -

Primary dilated cardiomyopathy;C0023976:Long QT syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

Jul 10, 2014

- -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 20, 2023

ClinVar contains an entry for this variant (Variation ID: 16845). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individuals with clinical features of Carvajal syndrome (PMID: 16467215, 30993396). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1267*) 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). -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 21, 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 with skin biopsies from carrier individuals has shown that this variant causes an absent expression of the major DSP transcript (NM_004415) in the heart (PMID: 16467215). This variant has been reported in homozygous state in an individual affected with arrhythmogenic cardiomyopathy with epidermolytic palmoplantar keratoderma and wooly hair (PMID: 16467215), and in compound heterozygous state with another DSP pathogenic variant in an individual affected with arrhythmogenic-dilated cardiomyopathy with epidermolytic palmoplantar keratoderma and wooly hair (PMID: 30993396). This variant has also been reported in compound heterozygous state with a DSP variant of uncertain significance in two twin brothers affected with early-onset dilated cardiomyopathy (PMID: 30398466), and in heterozygous state in an individual suspected of having hereditary cardiomyopathy (PMID: 35083019) as well as in five asymptomatic individuals (PMID: 16467215, 30398466, 30993396). This variant has not been identified 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 10, 2022

Reported in the heterozygous state in association with DCM and arrhythmogenic cardiomyopathy; however, patient-specific details were not provided (Marschall et al., 2019; Reza et al., 2022); 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: 25525159, 16467215, 34426522, 30398466, 31737537, 30993396, 31073624, 34691145, 35083019) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 23, 2023

The p.R1267* pathogenic mutation (also known as c.3799C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 3799. This changes the amino acid from an arginine to a stop codon within coding exon 23. 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 particular variant has been reported in the homozygous state in a subject with left and right ventricular involvement, wooly hair and palmar keratoderma (Uzumcu A et al. J. Med. Genet., 2006 Feb;43:e5). This variant has also been reported in the compound heterozygous state in two siblings with dilated cardiomyopathy (DCM) (Surmacz R et al. Pol. Arch. Intern. Med., 2018 12;128:785-787). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A
Vest4		0.91
GERP RS		4.3
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: rs121912997; hg19: chr6-7580222;