rs1554108859

Variant names:

• chr6-7583727-T-TA
• rs1554108859
• NM_004415.4:c.6466dupA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_004415.4(DSP):​c.6466dupA​(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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 14 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 15 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 [Likely_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 rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.6466dupA	p.Arg2156LysfsTer9	frameshift_variant	Exon 24 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.5137dupA	p.Arg1713LysfsTer9	frameshift_variant	Exon 24 of 24		NP_001305963.1
DSP	NM_001008844.3	c.4669dupA	p.Arg1557LysfsTer9	frameshift_variant	Exon 24 of 24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.6466dupA	p.Arg2156LysfsTer9	frameshift_variant	Exon 24 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.4669dupA	p.Arg1557LysfsTer9	frameshift_variant	Exon 24 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.5137dupA	p.Arg1713LysfsTer9	frameshift_variant	Exon 24 of 24			ENSP00000518230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Oct 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DSP c.6466dup; p.Arg2156LysfsTer9 variant (rs1554108859, ClinVar Variation ID: 419496) is reported in the literature in one individual from a genomic screening cohort who did not report arrhythmogenic cardiomyopathy (ACM); however, a portion of individuals in this cohort exhibited some features of ACM (Carruth 2021). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the DSP gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated DSP protein. Additionally, several downstream truncating variants have been described in individuals with cardiomyopathy and are considered pathogenic (Castelletti 2017, Smith 2020). Based on available information, this variant is considered to be likely pathogenic. References: Carruth ED et al. Clinical Findings and Diagnostic Yield of Arrhythmogenic Cardiomyopathy Through Genomic Screening of Pathogenic or Likely Pathogenic Desmosome Gene Variants. Circ Genom Precis Med. 2021 Apr;14(2):e003302. PMID: 33684294. Castelletti et al. Desmoplakin missense and non-missense mutations in arrhythmogenic right ventricular cardiomyopathy: Genotype-phenotype correlation. Int J Cardiol. 2017 Dec 15;249:268-273. PMID: 28527814. Smith et al. Desmoplakin Cardiomyopathy, a Fibrotic and Inflammatory Form of Cardiomyopathy Distinct From Typical Dilated or Arrhythmogenic Right Ventricular Cardiomyopathy. Circulation. 2020 Jun 9;141(23):1872-1884. PMID: 32372669 -

Jul 27, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Oct 03, 2022

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.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. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DSP-related conditions. ClinVar contains an entry for this variant (Variation ID: 419496). 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. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Dec 16, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;