chr6-7567366-ACT-A

Variant names:

• chr6-7567366-ACT-A
• rs1249913357
• NM_004415.4:c.1060_1061delCT

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_004415.4(DSP):​c.1060_1061delCT​(p.Leu354AlafsTer15) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• 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: 6.08

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 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.1060_1061delCT	p.Leu354AlafsTer15	frameshift_variant	Exon 9 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1060_1061delCT	p.Leu354AlafsTer15	frameshift_variant	Exon 9 of 24		NP_001305963.1
DSP	NM_001008844.3	c.1060_1061delCT	p.Leu354AlafsTer15	frameshift_variant	Exon 9 of 24		NP_001008844.1
DSP	NM_001406591.1	c.1060_1061delCT	p.Leu354AlafsTer15	frameshift_variant	Exon 9 of 11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1060_1061delCT	p.Leu354AlafsTer15	frameshift_variant	Exon 9 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.1060_1061delCT	p.Leu354AlafsTer15	frameshift_variant	Exon 9 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.1060_1061delCT	p.Leu354AlafsTer15	frameshift_variant	Exon 9 of 24			ENSP00000518230.1
DSP	ENST00000682228.1	n.384_385delCT		non_coding_transcript_exon_variant	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1

Jun 09, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 2 nucleotides in exon 9 of the DSP gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID 31386562). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

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

Dec 31, 2024

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.Leu354Alafs*15) 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 DSP-related conditions (PMID: 31386562). ClinVar contains an entry for this variant (Variation ID: 464956). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Jun 09, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1060_1061delCT variant, located in coding exon 9 of the DSP gene, results from a deletion of two nucleotides at nucleotide positions 1060 to 1061, causing a translational frameshift with a predicted alternate stop codon (p.L354Afs*15). This variant has been detected in an individual reported to have arrhythmogenic right ventricular cardiomyopathy (van Lint FHM et al. Circ Genom Precis Med, 2019 Aug;12:e002467). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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

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: rs1249913357; hg19: chr6-7567599;