rs727502993

Positions:

• chr6-7555752-A-AAC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004415.4(DSP):​c.208_209dup​(p.Ile71ProfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.75

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 12 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 6-7555752-A-AAC is Pathogenic according to our data. Variant chr6-7555752-A-AAC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 163230.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.208_209dup	p.Ile71ProfsTer13	frameshift_variant	2/24	ENST00000379802.8	NP_004406.2
DSP	NM_001008844.3	c.208_209dup	p.Ile71ProfsTer13	frameshift_variant	2/24		NP_001008844.1
DSP	NM_001319034.2	c.208_209dup	p.Ile71ProfsTer13	frameshift_variant	2/24		NP_001305963.1
DSP	NM_001406591.1	c.208_209dup	p.Ile71ProfsTer13	frameshift_variant	2/11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.208_209dup	p.Ile71ProfsTer13	frameshift_variant	2/24	1	NM_004415.4	ENSP00000369129	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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

Feb 27, 2014

The Ile71fs variant in DSP has not been previously reported in individuals with cardiomyopathy or in large population studies. This frameshift variant is predic ted to alter the protein?s amino acid sequence beginning at position 71 and lead ing to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the DSP gene is an established disease mechanism in individuals wit h ARVC and DCM. In summary, this variant is likely to be pathogenic, though addi tional studies are required to fully establish its clinical significance. -

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: rs727502993; hg19: chr6-7555985;