rs774763657

Positions:

• chr6-7582940-ACAGT-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_004415.4(DSP):​c.5680_5683del​(p.Ser1894LeufsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N1893N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 1.38

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 11 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 94 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7582940-ACAGT-A is Pathogenic according to our data. Variant chr6-7582940-ACAGT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 405232.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=1, Likely_pathogenic=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.5680_5683del	p.Ser1894LeufsTer34	frameshift_variant	24/24	ENST00000379802.8
DSP	NM_001008844.3	c.3883_3886del	p.Ser1295LeufsTer34	frameshift_variant	24/24
DSP	NM_001319034.2	c.4351_4354del	p.Ser1451LeufsTer34	frameshift_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.5680_5683del	p.Ser1894LeufsTer34	frameshift_variant	24/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.3883_3886del	p.Ser1295LeufsTer34	frameshift_variant	24/24	1		A2
DSP	ENST00000710359.1	c.4351_4354del	p.Ser1451LeufsTer34	frameshift_variant	24/24			A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251232 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461870 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 04, 2022	The DSP c.5680_5683delAGTC; p.Ser1894LeufsTer34 variant (rs774763657) is reported in the literature in an individual diagnosed with arrhythmogenic right ventricular cardiomyopathy (Ye 2019) and is reported as pathogenic/likely pathogenic in ClinVar (Variation ID: 405232). This variant is found on only three chromosomes in the Genome Aggregation Database (3/251,232 alleles), 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 protein missing the last 978 amino acids of the normal DSP protein. Truncating variants downstream of c.5680_5683delAGTC are reported in patients with cardiomyopathy and are considered disease-causing (Castelletti 2017, Fressart 2010). Based on available information, the c.5680_5683delAGTC variant is considered to be likely pathogenic. References: Castelletti S 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. Fressart V et al. Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice. Europace. 2010 Jun;12(6):861-8. Ye JZ et al. Reevaluation of genetic variants previously associated with arrhythmogenic right ventricular cardiomyopathy integrating population-based cohorts and proteomics data. Clin Genet. 2019 Dec;96(6):506-514. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2023	Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Reported as part of a multi-database review of ARVC-related variants; no clinical information was provided (PMID: 31402444); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11063735, 31402444) -

Cardiomyopathy Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 16, 2023	This variant deletes 4 nucleotides in exon 24 of the DSP gene, creating a frameshift and premature translation stop signal in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing an altered C-terminal sequence. Although functional studies have not been reported, this variant is expected to disrupt the plakin repeat domains and downstream C-terminal sequence, which have been reported to be essential for interaction with intermediate filaments (PMID: 12101406, 12802069, 21756917). In addition, truncating variants occurring downstream of this variant are known to be disease-causing (for example, ClinVar variation ID: 199903, 222582). To our knowledge, this variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/251232 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 08, 2024

This variant deletes 4 nucleotides in exon 24 of the DSP gene, creating a frameshift and premature translation stop signal in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing an altered C-terminal sequence. Although functional studies have not been reported, this variant is expected to disrupt the plakin repeat domains and downstream C-terminal sequence, which have been reported to be essential for interaction with intermediate filaments (PMID: 12101406, 12802069, 21756917). In addition, truncating variants occurring downstream of this variant are known to be disease-causing (for example, ClinVar variation ID: 199903, 222582). To our knowledge, this variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/251232 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

This sequence change creates a premature translational stop signal (p.Ser1894Leufs*34) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 978 amino acid(s) of the DSP protein. This variant is present in population databases (rs774763657, gnomAD 0.009%). 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: 405232). This variant disrupts a region of the DSP protein in which other variant(s) (p.Thr2634Lysfs*4) have been determined to be pathogenic (PMID: 11063735). 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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2024

The c.5680_5683delAGTC pathogenic mutation, located in coding exon 24 of the DSP gene, results from a deletion of 4 nucleotides at nucleotide positions 5680 to 5683, causing a translational frameshift with a predicted alternate stop codon (p.S1894Lfs*34). 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. As such, this alteration is interpreted as a disease-causing mutation. -

Familial isolated arrhythmogenic right ventricular dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 21, 2023

Variant summary: DSP c.5680_5683delAGTC (p.Ser1894LeufsX34) results in a premature termination codon and is predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. Although the variant is not predicted to cause absence of the protein through nonsense mediated decay, the variant is predicted to disrupt the last 978 amino acids in the protein sequence. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251232 control chromosomes (gnomAD). To our knowledge, no occurrence of c.5680_5683delAGTC in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters have assessed the variant since 2014: three classified the variant as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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: rs774763657; hg19: chr6-7583173;