6-7581012-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.4822C>T(p.Gln1608Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DSP NM_004415.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.68

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 6-7581012-C-T is Pathogenic according to our data. Variant chr6-7581012-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 405234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.4822C>T	p.Gln1608Ter	stop_gained	23/24	ENST00000379802.8
DSP	NM_001008844.3	c.3582+1240C>T		intron_variant
DSP	NM_001319034.2	c.4050+772C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.4822C>T	p.Gln1608Ter	stop_gained	23/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.3582+1240C>T		intron_variant		1		A2
DSP	ENST00000710359.1	c.4050+772C>T		intron_variant				A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461688 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727124

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

This sequence change creates a premature translational stop signal (p.Gln1608*) 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 clinical features of DSP-related conditions (PMID: 32372669). ClinVar contains an entry for this variant (Variation ID: 405234). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

May 17, 2017

p.Gln1608* (c.4822C>T) in exon 23 of the DSP gene (NM_004415.2) Given that this is a truncating variant in a gene in which haploinsufficiency is a known mechanism of disease, and its association with both arrhythmogenic right ventricular cardiomyopathy (ARVC) and non-ischemic dilated cardiomyopathy (DCM), we consider this variant likely disease-causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). DSP is associated with both ARVC and DCM. This is a novel variant and does not have an entry in ClinVar. However, the majority of the mutations in the DSP gene associated with ARVC and DCM are nonsense or frameshift mutations (Stenson P et al., 2009). haploinsufficiency is a known mechanism of disease (Yang et al 2006). Furthermore, in the ExAC constraint analyses indicates DSP is intolerant to loss of function/truncating variation (pLI - 1.000) and cardiodb.org lists truncating variants in DSP enriched both cases of ARVC and DCM vs. controls. Walsh et al (2016) found that truncating DSP variants were enriched in cases of DCM over ExAC controls with odds ration of 41.0. The c-terminal end of the protein, which is altered by this frameshift, is important for protein interactions with IFs to anchor them to the desmosome (Kouklis et al. 1994; Bornslaeger et al. 1996). Groeneweg et al. (2016) reports on 1001 ARVC index patients from the Hopkins cohort. Nine of eleven index patients have either nonsense or frameshift variants in the DSP gene. Sen-Chowdry et a. (2007) noted that 68 of their 200 patients presenting to ARVC clinic had left ventricular wall abnormalities, with septal hypokinesia the most common. Although the heart function was abnormal, there was no evidence for involvement of ARVC in the LV. 68 of these patients had LV dilation and 31 had a reduced LVEF. Lopez-Ayala et al. (2014) reported on the outcome of sequencing DSP in 47 patients with either DCM or ARVC who presented with either arrhythmia or sudden cardiac arrest/death. Three of these probands were found to have the same truncating variant in DSP (c.1339C>T - not our patients' familial variant). 15 relatives were found to be carriers after cascade genetic screening. The first symptoms were: sustained VT in 6 carriers and left ventricular impairment in 9. MRI noted LV involvement in 9 cases and biventricular disease in 3. Fibrosis was seen in 6 family members and non-compaction in 5. In the first family, the 37 years old proband presented with an episode of sustained VT at rest. An echocardiogram showed LV dilation and systolic dysfunction. His mother was diagnosed with idiopathic DCM at 67 years old after ruling out coronary artery disease. The maternal grandfather died in his sleep at 37 years old after suffering from heart failure. Other family members, including 2 siblings, have since developed symptoms. The two siblings had progressive systolic dysfunction. In the second family, the 42 years old proband presented with a pre-syncopal episode of sustained VT and echocardiogram noted global LV hypokinesia and moderately impaired systolic dysfunction. Her 72 years old mother's echocardiogram showed severe systolic impairment without CAD. A maternal aunt died suddenly at 40 years old. The third family's proband, a 62 years old woman, presented with acute heart failure and an echocardiogram showed moderately impaired systolic function and MRI results led to the diagnosis of LVNC. Her daughter had "myocarditis" at 32 years old and his 45 year old nephew presented with cardiac arrest while walking. His nephew was diagnosed with LVNC and moderate systolic dysfunction. The glutamine at codon 1608 is moderately conserved across species, as are neighboring amino acids. This variant is not present in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 urelated individuals of African, Asian, European, Latino, an -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2018

The p.Q1608* pathogenic mutation (also known as c.4822C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 4822. This changes the amino acid from a glutamine 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 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	0.62	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A;D
Vest4		0.92
GERP RS		5.9
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060500610; hg19: chr6-7581245;