chr6-7585336-CAGAA-C

Position:

• chr6-7585336-CAGAA-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_004415.4(DSP):​c.8077_8080delAAAG​(p.Lys2693fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.32

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 does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0626 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PP5: Variant 6-7585336-CAGAA-C is Pathogenic according to our data. Variant chr6-7585336-CAGAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 246676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7585336-CAGAA-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.8077_8080delAAAG	p.Lys2693fs	frameshift_variant	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.6748_6751delAAAG	p.Lys2250fs	frameshift_variant	24/24		NP_001305963.1
DSP	NM_001008844.3	c.6280_6283delAAAG	p.Lys2094fs	frameshift_variant	24/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.8077_8080delAAAG	p.Lys2693fs	frameshift_variant	24/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.6280_6283delAAAG	p.Lys2094fs	frameshift_variant	24/24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.6748_6751delAAAG	p.Lys2250fs	frameshift_variant	24/24			ENSP00000518230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461878 Hom.: 0 AF XY: 0.00000963 AC XY: 7 AN XY: 727236

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: 0.0000126

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 24, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ARVC (MIM#607450) and other DSP-related cardiac disorders. (I) 0108 - This gene is associated with both recessive and dominant disease. Variants in this gene are usually inherited in a dominant manner, however rare reports of recessive inheritance have resulted in a more severe cardiac phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Age-dependent penetrance and variable expressivity are well-described aspects of arrhythmogenic cardiomyopathy (PMID: 29062697). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0701 - Other truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in ClinVar. It has also been reported in two individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 28527814, 27532257). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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

Oct 29, 2019

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the DSP protein. Other variant(s) that disrupt this region (p.Glu2728Glyfs*11) have been determined to be pathogenic (Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 28527814, 27532257). ClinVar contains an entry for this variant (Variation ID: 246676). This sequence change results in a premature translational stop signal in the DSP gene (p.Lys2693Profs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 179 amino acids of the DSP protein. -

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: rs879254352; hg19: chr6-7585569;