rs727505077

chr6-7571431-GA-G

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.1751del(p.Glu584GlyfsTer52) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.95

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 6-7571431-GA-G is Pathogenic according to our data. Variant chr6-7571431-GA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.1751del	p.Glu584GlyfsTer52	frameshift_variant	14/24	ENST00000379802.8
DSP	NM_001319034.2	c.1751del	p.Glu584GlyfsTer52	frameshift_variant	14/24
DSP	NM_001008844.3	c.1751del	p.Glu584GlyfsTer52	frameshift_variant	14/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.1751del	p.Glu584GlyfsTer52	frameshift_variant	14/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.1751del	p.Glu584GlyfsTer52	frameshift_variant	14/24	1		A2
DSP	ENST00000710359.1	c.1751del	p.Glu584GlyfsTer52	frameshift_variant	14/24			A2
DSP	ENST00000684395.1	n.135del		non_coding_transcript_exon_variant	2/5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727242

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 06, 2021

The p.Glu584GlyfsX52 variant in DSP has been identified by our laboratory in 1 individual with dilated cardiomyopathy (DCM) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 584 and lead to a premature termination codon 52 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the DSP gene is an established disease mechanism in autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) and autosomal recessive Carvajal syndrome. DSP loss of function variants have also been reported in individuals with DCM. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant ARVC (which can present with DCM) and autosomal recessive Carvajal syndrome. ACMG/AMP criteria applied: PVS1, PM2_Supporting. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2023

The c.1751delA pathogenic mutation, located in coding exon 14 of the DSP gene, results from a deletion of one nucleotide at nucleotide position 1751, causing a translational frameshift with a predicted alternate stop codon (p.E584Gfs*52). This variant has been detected in a cohort of patients from referral centers seeing patients for dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy diagnoses; however, details were limited (Smith ED et al. Circulation. 2020 Jun;141(23):1872-1884). 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)		0.0		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: rs727505077; hg19: chr6-7571664;