6-7571554-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.1873C>T(p.Gln625Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,882 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: 0.0000014 (0 hom.)
• Consequence: DSP NM_004415.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.49

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 6-7571554-C-T is Pathogenic according to our data. Variant chr6-7571554-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228253.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.1873C>T	p.Gln625Ter	stop_gained	14/24	ENST00000379802.8
DSP	NM_001319034.2	c.1873C>T	p.Gln625Ter	stop_gained	14/24
DSP	NM_001008844.3	c.1873C>T	p.Gln625Ter	stop_gained	14/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.1873C>T	p.Gln625Ter	stop_gained	14/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.1873C>T	p.Gln625Ter	stop_gained	14/24	1		A2
DSP	ENST00000710359.1	c.1873C>T	p.Gln625Ter	stop_gained	14/24			A2
DSP	ENST00000684395.1	n.257C>T		non_coding_transcript_exon_variant	2/5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely 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

Jul 26, 2019

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). This variant has been observed in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 21606390). ClinVar contains an entry for this variant (Variation ID: 228253). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln625*) in the DSP gene. It is expected to result in an absent or disrupted protein product. -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 15, 2015

The p.Gln625X variant in DSP has been reported in 1 individual with ARVC (Quarta 2011) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 625 which is predicted to lead to a truncated or absent protein. Frameshift and nonsense variants in DSP have been reported in patients with ARVC (http://arvcdatabase.info/), but recent evidence supports that they can also cause DCM (Pugh 2014). In summary, although additio nal studies are required to fully establish its clinical significance, the p.Gln 625X variant is likely pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2019

The p.Q625* pathogenic mutation (also known as c.1873C>T), located in coding exon 14 of the DSP gene, results from a C to T substitution at nucleotide position 1873. This changes the amino acid from a glutamine to a stop codon within coding exon 14. This variant has been reported in arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts (Quarta G et al. Circulation, 2011 Jun;123:2701-9; Castelletti S et al. Int. J. Cardiol., 2017 Dec;249:268-273). Alterations in DSP that result in haploinsufficiency or protein truncation have been reported in patients with 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	0.66
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A
Vest4		0.89
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs876657638; hg19: chr6-7571787; COSMIC: COSV101131165;