6-7577007-CA-CAA

Position:

• chr6-7577007-CA-CAA

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.2848dupA​(p.Ile950fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. 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: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.70

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 6-7577007-C-CA is Pathogenic according to our data. Variant chr6-7577007-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.2848dupA	p.Ile950fs	frameshift_variant	20/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.2848dupA	p.Ile950fs	frameshift_variant	20/24		NP_001305963.1
DSP	NM_001008844.3	c.2848dupA	p.Ile950fs	frameshift_variant	20/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.2848dupA	p.Ile950fs	frameshift_variant	20/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.2848dupA	p.Ile950fs	frameshift_variant	20/24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.2848dupA	p.Ile950fs	frameshift_variant	20/24			ENSP00000518230.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

clinical testing

KTest Genetics, KTest

-

- -

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

Apr 24, 2023

This sequence change creates a premature translational stop signal (p.Ile950Asnfs*3) in the DSP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 44885). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 27532257). -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 25, 2012

The Ile950fs variant in DSP has not been reported in the literature nor previous ly identified by our laboratory. This frameshift variant is predicted to alter t he protein?s amino acid sequence beginning at position 950 and lead to a prematu re termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Frameshift and nonsense variants in D SP have been reported in patients with ARVC (http://arvcdatabase.info/), but rec ent evidence supports that they can also cause DCM (Elliott 2010, Garcia-Pavia 2 011). In summary, this variant is likely to be pathogenic, though segregation st udies and functional analyses are required to fully establish its pathogenicity. -

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: rs397516927; hg19: chr6-7577240;