rs397516913

Positions:

• chr6-7567780-GT-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000379802.8(DSP):​c.1146del​(p.Phe382LeufsTer11) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP ENST00000379802.8 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.99

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 6-7567780-GT-G is Pathogenic according to our data. Variant chr6-7567780-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 44852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7567780-GT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.1146del	p.Phe382LeufsTer11	frameshift_variant, splice_region_variant	10/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1146del	p.Phe382LeufsTer11	frameshift_variant, splice_region_variant	10/24		NP_001305963.1
DSP	NM_001008844.3	c.1146del	p.Phe382LeufsTer11	frameshift_variant, splice_region_variant	10/24		NP_001008844.1
DSP	NM_001406591.1	c.1146del	p.Phe382LeufsTer11	frameshift_variant, splice_region_variant	10/11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1146del	p.Phe382LeufsTer11	frameshift_variant, splice_region_variant	10/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.1146del	p.Phe382LeufsTer11	frameshift_variant, splice_region_variant	10/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.1146del	p.Phe382LeufsTer11	frameshift_variant, splice_region_variant	10/24			ENSP00000518230	A2
DSP	ENST00000682228.1	n.801del		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 20, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 44852). This premature translational stop signal has been observed in individual(s) with DSP-related conditions (PMID: 32372669). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe382Leufs*11) 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). -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 21, 2019

The p.Phe382LeufsX11 variant in DSP has been identified 7 individuals with DSP-associated cardiomyopathy (6 DCM, 1 ARVC, 1 LVNC/PVCs) including 1 obligate carrier, from 1 family. Two of these individuals had childhood onset disease and carried an additional variant of uncertain significance in DSP in trans (p.Arg315Cys; LMM data).The p.Phe382LeufsX11 variant was absent from large population studies. This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 382 and lead to a premature termination codon 11 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 ARVC and autosomal recessive Carvajal syndrome. 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, PP1_Moderate. -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 17, 2023

This variant deletes 1 nucleotide in exon 10 of the DSP gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, or left ventricular non-compaction (PMID: 32372669, ClinVar SCV000061651.6). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 2
DS_AL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397516913; hg19: chr6-7568013;