6-7571554-C-T

Variant names:

• chr6-7571554-C-T
• rs876657638
• NM_004415.4:c.1873C>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.Gln625*) 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 rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.1873C>T	p.Gln625*	stop_gained	Exon 14 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1873C>T	p.Gln625*	stop_gained	Exon 14 of 24		NP_001305963.1
DSP	NM_001008844.3	c.1873C>T	p.Gln625*	stop_gained	Exon 14 of 24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1873C>T	p.Gln625*	stop_gained	Exon 14 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.1873C>T	p.Gln625*	stop_gained	Exon 14 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.1873C>T	p.Gln625*	stop_gained	Exon 14 of 24			ENSP00000518230.1
DSP	ENST00000684395.1	n.257C>T		non_coding_transcript_exon_variant	Exon 2 of 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

Jul 26, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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). -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Oct 15, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 26, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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;