rs1554108859

Positions:

• chr6-7583727-T-TA

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.6466dup​(p.Arg2156LysfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D2155D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.20

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 does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 66 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7583727-T-TA is Pathogenic according to our data. Variant chr6-7583727-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 419496.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.6466dup	p.Arg2156LysfsTer9	frameshift_variant	24/24	ENST00000379802.8
DSP	NM_001008844.3	c.4669dup	p.Arg1557LysfsTer9	frameshift_variant	24/24
DSP	NM_001319034.2	c.5137dup	p.Arg1713LysfsTer9	frameshift_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.6466dup	p.Arg2156LysfsTer9	frameshift_variant	24/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.4669dup	p.Arg1557LysfsTer9	frameshift_variant	24/24	1		A2
DSP	ENST00000710359.1	c.5137dup	p.Arg1713LysfsTer9	frameshift_variant	24/24			A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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 03, 2022

This variant has not been reported in the literature in individuals affected with DSP-related conditions. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DSP protein in which other variant(s) (p.Arg2166*, p.Gly2414*, p.Ser2168Argfs*18) have been determined to be pathogenic (PMID: 23671136, 27532257; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 419496). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2156Lysfs*9) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 716 amino acid(s) of the DSP protein. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2015

Although the c.6466dupA duplications in the DSP gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Arginine 2156, changing it to a Lysine, and creating apremature stop codon at position 9 of the new reading frame, denoted p.Arg2156LysfsX9. This duplication isexpected to result in an abnormal, truncated protein product with the last 716 correct amino acids beingreplaced by 8 incorrect amino acids. Other frameshift variants in the DSP gene have been reported inHGMD in association with cardiomyopathy (Stenson P et al., 2014). Furthermore, the c.6466dupA duplicationwas not observed in approximately 6,500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.6466dupA in the DSP gene is interpreted as a pathogenic variant. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2022

The c.6466dupA pathogenic mutation, located in coding exon 24 of the DSP gene, results from a duplication of A at nucleotide position 6466, causing a translational frameshift with a predicted alternate stop codon (p.R2156Kfs*9). This alteration occurs at the 3' terminus of theDSP gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 716 amino acids (25%) of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). 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 variant has been detected in an individual from an exome sequencing cohort without overt ARVC; however, a portion of individuals in this cohort exhibited some features of ARVC or DCM (Carruth ED et al. Circ Genom Precis Med. 2021 Apr;14(2):e003302). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

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: rs1554108859; hg19: chr6-7583960;