6-7580388-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_004415.4(DSP):c.4198C>T(p.Arg1400*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,868 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R1400R) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

DSP
NM_004415.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: -0.300

Variant links:

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]

DSP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 6-7580388-C-T is Pathogenic according to our data. Variant chr6-7580388-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 199884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4 link	c.4198C>T	p.Arg1400*	stop_gained	Exon 23 of 24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 link	c.4050+148C>T		intron_variant	Intron 23 of 23		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 link	c.3582+616C>T		intron_variant	Intron 23 of 23		NP_001008844.1	P15924-2B4DKX6Q4LE79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DSP	ENST00000379802.8 link	c.4198C>T	p.Arg1400*	stop_gained	Exon 23 of 24	1	NM_004415.4	ENSP00000369129.3	P15924-1
DSP	ENST00000418664.2 link	c.3582+616C>T		intron_variant	Intron 23 of 23	1		ENSP00000396591.2	P15924-2
DSP	ENST00000710359.1 link	c.4050+148C>T		intron_variant	Intron 23 of 23			ENSP00000518230.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151982

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251250

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151982

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 8

Pathogenic:3

Jan 17, 2023

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4198C>T variant identified in this individual has previously been reported in at least two individuals with arrhythmogenic right ventricular cardiomyopathy [PMID: 24125834, 29178656], in an individual with dilated cardiomyopathy [PMID: 33996946], and in a 3-year-old boy affected with severe heart failure and cutaneous abnormalities in compound heterozygosity with p.(Arg2284Ter) [PMID: 25516398]. The c.4198C>T variant has been deposited in ClinVar [ClinVar ID: 199884] as Pathogenic (8 entries) and Likely Pathogenic (1 entry). The c.4198C>T variant is observed in 4 alleles (0.0006% minor allele frequency with 0homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.4198C>T variant is located in exon 23 of this 24-exon gene, predicted to incorporate a premature termination codon (p.(Arg1400Ter)), and is expected to result in loss-of-function via nonsense-mediated decay. Based on available evidence this c.4198C>T p.(Arg1400Ter) variant identified in DSP is classified as Pathogenic. -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ARVC (MIM#607450) and other DSP-related cardiac disorders. (I) 0108 - This gene is associated with both recessive and dominant disease. Variants in this gene are usually inherited in a dominant manner, however rare reports of recessive inheritance have resulted in a more severe cardiac phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Age-dependent penetrance and variable expressivity are well-described aspects of arrhythmogenic cardiomyopathy (PMID: 29062697). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3, v2) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. NMD-predicted variants are well-reported pathogenic in this gene (ClinVar, PMID: 30382575). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is reported as pathogenic or likely pathogenic in ClinVar. It has also been reported in the literature in individuals with ARVD and early onset heart failure with cutaneous abnormalities (PMID: 24125834, 25516398). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Feb 26, 2018

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Pathogenic:2

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 04, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Identified in the heterozygous state in patients with ARVC and DCM referred for genetic testing at GeneDx and in published literature (PMID: 24125834, 29178656, 32877757, 33996946, 36264615); Observed with a pathogenic variant in an individual in the literature with both cardiac and cutaneous manifestations of a DSP-related disorder and familial testing suggests the variants are likely present on opposite alleles (in trans) (PMID: 25516398); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31402444, 34135346, 32877757, 33996946, 35130036, 36437915, 24125834, 29178656, 36264615, 25516398) -

Dilated cardiomyopathy 1A

Pathogenic:2

Dec 26, 2022

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

We observed a homozygous c.4198C>T (p.R1400*) genetic variant in the DSP gene in a 4-y.o. female proband (of consanguineous marriage) diagnosed with dilated cardiomyopathy and thrombosis. According to NMD Esc Predictor, mRNA carrying this variant will be processed through nonsense-mediated decay mechanism, leading to haploinsufficiency. This variant is not observed at significant frequency in large population cohorts (gnomAD). ClinVar contains an entry for this variant (Variation ID: 199884). This genetic variant in heterozygous state was reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24125834, 29178656), and in a 3-y.o. male proband affected with severe heart failure and cutaneous abnormalities in compound heterozygosity with p.Arg2284* (PMID: 25516398). For these reasons, this variant has been classified as Pathogenic. -

Feb 04, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg1400*) 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 present in population databases (rs770873593, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy and/or desmosomal cardiocutaneous syndromes (PMID: 24125834, 25516398). ClinVar contains an entry for this variant (Variation ID: 199884). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy

Pathogenic:1

Nov 09, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 23 of the DSP gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant. This variant was reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24125834, 29178656), and in a 3-year-old boy affected with severe heart failure and cutaneous abnormalities in compound heterozygosity with p.Arg2284* (PMID: 25516398). This variant has been identified in 1/246122 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

May 26, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1400* pathogenic mutation (also known as c.4198C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 4198. This changes the amino acid from an arginine to a stop codon within coding exon 23. This mutation has been detected once in an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort as well as in a three year old male with left-sided heart failure, cutaneous abnormalities, and palmoplantar keratoderma (PPK) who also carried DSP R2284* (Bao J et al. Circ Cardiovasc Genet, 2013 Dec;6:552-6; Antonov NK et al. Pediatr Dermatol Dec;32:102-8). In addition to the clinical data presented in the literature, alterations in DSP that result in haploinsufficiency or protein truncation have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM) (Fressart V et al. Europace. 2010;12(6):861-8; Elliott P et al. Circ Cardiovasc Genet. 2010;3(4):314-22; Quarta G et al. Circulation. 2011;123(23):2701-9; Garcia-Pavia P et al. Heart. 2011;97(21):1744-52; Rasmussen TB et al. Clin Genet. 2013;84(1):20-30; Pugh TJ et al. Genet Med. 2014;16(8):601-8). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1+PS4_Supporting -

Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

Pathogenic:1

Aug 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Benign

0.93

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.32

Vest4

0.88

GERP RS

-7.6

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over