rs397514039

chr6-7584883-AG-Achr6-7584883-AG-AGG

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.7623del(p.Lys2542SerfsTer19) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R2541R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.49

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 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 30 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7584883-AG-A is Pathogenic according to our data. Variant chr6-7584883-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 16837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7584883-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.7623del	p.Lys2542SerfsTer19	frameshift_variant	24/24	ENST00000379802.8
DSP	NM_001319034.2	c.6294del	p.Lys2099SerfsTer19	frameshift_variant	24/24
DSP	NM_001008844.3	c.5826del	p.Lys1943SerfsTer19	frameshift_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.7623del	p.Lys2542SerfsTer19	frameshift_variant	24/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.5826del	p.Lys1943SerfsTer19	frameshift_variant	24/24	1		A2
DSP	ENST00000710359.1	c.6294del	p.Lys2099SerfsTer19	frameshift_variant	24/24			A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 27, 2021	Variant summary: DSP c.7623delG (p.Lys2542SerfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251490 control chromosomes (gnomAD). c.7623delG has been reported in the literature in multiple homozygous individuals affected with Carvajal Syndrome (Norgett_2000). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2000	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 16837). This variant is also known as 7901delG. This premature translational stop signal has been observed in individuals with Carvajal syndrome (PMID: 11063735). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys2542Serfs*19) in the DSP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 330 amino acid(s) of the DSP protein. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 08, 2019

Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11063735, 25227139, 14761782, 8769422) -

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: rs397514039; hg19: chr6-7585116;