rs397516915

Positions:

• chr6-7568443-C-T

Variant summary

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

The ENST00000379802.8(DSP):​c.1273C>T​(p.Arg425Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DSP ENST00000379802.8 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.44

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 6-7568443-C-T is Pathogenic according to our data. Variant chr6-7568443-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44856.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.1273C>T	p.Arg425Ter	stop_gained	11/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1273C>T	p.Arg425Ter	stop_gained	11/24		NP_001305963.1
DSP	NM_001008844.3	c.1273C>T	p.Arg425Ter	stop_gained	11/24		NP_001008844.1
DSP	NM_001406591.1	c.1273C>T	p.Arg425Ter	stop_gained	11/11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1273C>T	p.Arg425Ter	stop_gained	11/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.1273C>T	p.Arg425Ter	stop_gained	11/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.1273C>T	p.Arg425Ter	stop_gained	11/24			ENSP00000518230	A2
DSP	ENST00000682228.1	n.1458C>T		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251268 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135794

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461738 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 29, 2019	proposed classification - variant undergoing re-assessment, contact laboratory -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Apr 23, 2015	- -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 17, 2023

The c.1273C>T (p.Arg425*) variant in the DSP gene creates a premature translation stop codon. It is predicted to result in a disrupted protein product or absent protein due to nonsense mediated decay. This variant has been observed in patients affected with arrhythmogenic right ventricular cardiomyopathy/ dysplasia (ARVC/D) (PMID: 33821670, 22555271). This variant is rare (1/251268) alleles in the general population database, gnomAD. ClinVar has an entry for this variant (ID:44856). Loss-of-function variants in DSP gene are known to be pathogenic (PMID: 24503780, 20716751, 25227139). Therefore, the c.1273C>T (p.Arg425*) variant in the DSP gene is classified as pathogenic. -

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

Aug 01, 2023

This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 22555271). This variant is present in population databases (rs397516915, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg425*) 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). ClinVar contains an entry for this variant (Variation ID: 44856). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 28, 2015

- -

DSP-related arrhythmogenic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Aug 14, 2019

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 22, 2021

Identified in a family with ARVC in the published literature (Kindel et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar (ClinVar Variant ID# 44856; ClinVar); This variant is associated with the following publications: (PMID: 31402444, 22555271, 26582918, 27535533) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2024

The c.1273C>T (p.R425*) alteration, located in exon 11 (coding exon 11) of the DSP gene, consists of a C to T substitution at nucleotide position 1273. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 425. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of <0.001% (1/251268) total alleles studied. The highest observed frequency was 0.001% (1/113658) of European (non-Finnish) alleles. This variant was reported in an individual with familial arrhythmogenic right ventricular cardiomyopathy (ARVC) (Kindel, 2012). Based on the available evidence, this alteration is classified as pathogenic. -

Familial isolated arrhythmogenic right ventricular dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 28, 2023

Variant summary: DSP c.1273C>T (p.Arg425X) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251268 control chromosomes (gnomAD). c.1273C>T has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (Kindel_2012, Protonotarios_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22555271, 35766183, 35653365). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=3) and likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A
Vest4		0.95
GERP RS		4.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs397516915; hg19: chr6-7568676; COSMIC: COSV65792321; COSMIC: COSV65792321;