rs397516956

Variant names:

• chr6-7562762-C-CA
• rs397516956
• NM_004415.4:c.712dupA

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.712dupA​(p.Ile238AsnfsTer19) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.59

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 6-7562762-C-CA is Pathogenic according to our data. Variant chr6-7562762-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44948.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.712dupA	p.Ile238AsnfsTer19	frameshift_variant	Exon 5 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.712dupA	p.Ile238AsnfsTer19	frameshift_variant	Exon 5 of 24		NP_001305963.1
DSP	NM_001008844.3	c.712dupA	p.Ile238AsnfsTer19	frameshift_variant	Exon 5 of 24		NP_001008844.1
DSP	NM_001406591.1	c.712dupA	p.Ile238AsnfsTer19	frameshift_variant	Exon 5 of 11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.712dupA	p.Ile238AsnfsTer19	frameshift_variant	Exon 5 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.712dupA	p.Ile238AsnfsTer19	frameshift_variant	Exon 5 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.712dupA	p.Ile238AsnfsTer19	frameshift_variant	Exon 5 of 24			ENSP00000518230.1
DSP	ENST00000506617.1	n.230dupA		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Feb 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 44948). This variant has not been reported in the literature in individuals affected with DSP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile238Asnfs*19) 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). -

Primary dilated cardiomyopathy Pathogenic:1

Jul 17, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Ile238fs variant in DSP has not been reported in the literature nor previous ly identified by our laboratory. This frameshift variant is predicted to alter t he protein?s amino acid sequence beginning at position 238 and lead to a prematu re termination codon 19 amino acids downstream. This alteration is then predicte d to lead to a truncated or absent protein. In summary, this variant is likely t o be pathogenic, though additional studies are required to fully establish its c linical significance. Please note: Frameshift and nonsense variants in DSP are common in patients with ARVC (http://arvcdatabase.info/), but recent evidence su pports that they can also cause DCM (Elliott 2010, Garcia-Pavia 2011). -

Cardiovascular phenotype Pathogenic:1

Jul 22, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.712dupA variant, located in coding exon 5 of the DSP gene, results from a duplication of A at nucleotide position 712, causing a translational frameshift with a predicted alternate stop codon (p.I238Nfs*19). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. 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)		0.040		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: rs397516956; hg19: chr6-7562995;