6-7571431-GA-G

Variant names:

• chr6-7571431-GA-G
• rs727505077
• NM_004415.4:c.1751delA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004415.4(DSP):​c.1751delA​(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
• Publications: 2 publications found

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]

DSP Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 8

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• keratosis palmoplantaris striata 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp
• skin fragility-woolly hair-palmoplantar keratoderma syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
• arrhythmogenic cardiomyopathy with wooly hair and keratoderma

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Orphanet, Ambry Genetics
• cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• striate palmoplantar keratoderma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe dermatitis-multiple allergies-metabolic wasting syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 179720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7571431-GA-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 179720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7571431-GA-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 179720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7571431-GA-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 179720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7571431-GA-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 179720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7571431-GA-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 179720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7571431-GA-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 179720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7571431-GA-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 179720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7571431-GA-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 179720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7571431-GA-G is described in CliVar as Pathogenic/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 rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.1751delA	p.Glu584GlyfsTer52	frameshift_variant	Exon 14 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1751delA	p.Glu584GlyfsTer52	frameshift_variant	Exon 14 of 24		NP_001305963.1
DSP	NM_001008844.3	c.1751delA	p.Glu584GlyfsTer52	frameshift_variant	Exon 14 of 24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1751delA	p.Glu584GlyfsTer52	frameshift_variant	Exon 14 of 24	1	NM_004415.4	ENSP00000369129.3

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

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

Jan 06, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 10, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9

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

Other links and lift over

dbSNP: rs727505077; hg19: chr6-7571664;