6-7579922-G-GGAAAATC

Position:

• chr6-7579922-G-GGAAAATC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_004415.4(DSP):​c.3735_3741dup​(p.Asp1248LysfsTer7) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000616 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.67

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-7579922-G-GGAAAATC is Pathogenic according to our data. Variant chr6-7579922-G-GGAAAATC is described in ClinVar as [Pathogenic]. Clinvar id is 199923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.3735_3741dup	p.Asp1248LysfsTer7	frameshift_variant	23/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.3735_3741dup	p.Asp1248LysfsTer7	frameshift_variant	23/24		NP_001305963.1
DSP	NM_001008844.3	c.3582+153_3582+159dup		intron_variant			NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.3735_3741dup	p.Asp1248LysfsTer7	frameshift_variant	23/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.3582+153_3582+159dup		intron_variant		1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.3735_3741dup	p.Asp1248LysfsTer7	frameshift_variant	23/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250460 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135566

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461816 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727198

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Aug 16, 2023

The c.3735_3741dup (p.Asp1248Lysfs*7) variant of the DSP gene is predicted to cause shift of reading frame that results in a premature stop codon and an absent or disrupted protein product. This variant was detected in an individual with arrhythmogenic right ventricular cardiomyopathy (ARVC), and in two affected family members and two unaffected family members (PMID: 29062697). This variant has also been reported in an individual with DSP-related cardiomyopathy and an individual with dilated cardiomyopathy (DCM), although clinical details were limited (PMID: 27532257, 32372669). Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). This variant is extremely rare in the general population according to gnomAD. Therefore, the c.3735_3741dup (p.Asp1248Lysfs*7) variant in the DSP gene has been classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 22, 2023

This sequence change creates a premature translational stop signal (p.Asp1248Lysfs*7) 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 variant has not been reported in the literature in individuals affected with DSP-related conditions. ClinVar contains an entry for this variant (Variation ID: 199923). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 21, 2023

This variant inserts 7 nucleotides in exon 23 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 at least five unrelated individuals affected with arrhythmogenic cardiomyopathy or dilated cardiomyopathy (PMID: 27532257, 29062697, 31983221, 32372669). This variant has been identified in 1/250460 chromosomes 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 cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 23, 2019

The p.Asp1248LysfsX7 variant in DSP has been reported in 1 individual with DCM, monozygotic twin brothers with ARVC, and 1 individual with cardiomyopathy, AV block, and ventricular tachycardia (Docekal 2017, Walsh 2017, LMM data). It has also been identified in 0.001% (1/113054) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported as Pathogenic in ClinVar (Variation ID 199923). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1248 and leads to a premature termination codon 7 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. This variant is located within exon 23 of DSP, which undergoes alternative splicing to produce 3 isoforms: a short (DSPII), an intermediate (DSPIa), and a long (DSPI) form. This variant impacts the DSPI and DSPIa isoforms. The long DSPI transcript is the predominant isoform in cardiac tissue and multiple loss-of-function variants affecting this isoform have been identified in individuals with ARVC and/or DCM (Uzumcu 2006, Cabral 2010, LMM data). Loss of function of the DSP gene is an established disease mechanism in autosomal dominant ARVC and autosomal recessive Carvajal syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant ARVC and autosomal recessive Carvajal syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 27, 2023

Reported in association with a DSP-related cardiomyopathy (PMID: 27532257, 29062697, 32372669, 36264615); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32372669, 31402444, 29062697, 33087929, 34352074, 36264615, 27532257) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2021

The c.3735_3741dupAAATCGA pathogenic mutation, located in coding exon 23 of the DSP gene, results from a duplication of AAATCGA at nucleotide positions 3735 to 3741, causing a translational frameshift with a predicted alternate stop codon (p.D1248Kfs*7). 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 particular alteration was detected in an individual with arrhythmogenic right ventricular cardiomyopathy (ARVC), as well as in two affected family members and two unaffected family members (Docekal JW et al. HeartRhythm Case Rep, 2017 Oct;3:459-463). This variant has also been reported in a DSP-related cardiomyopathy cohort and in a cardiac genetic testing cohort, although clinical details were limited (Walsh R et al. Genet Med. 2017;19:192-203; Smith ED et al. Circulation, 2020 06;141:1872-1884). 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

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554108152; hg19: chr6-7580155;