6-7580388-C-T

Position:

chr6-7580388-C-T

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.Arg1400Ter) 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:10

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/exons	MANE	Protein
DSP	NM_004415.4 linkuse as main transcript	c.4198C>T	p.Arg1400Ter	stop_gained	23/24	ENST00000379802.8	NP_004406.2
DSP	NM_001008844.3 linkuse as main transcript	c.3582+616C>T		intron_variant			NP_001008844.1
DSP	NM_001319034.2 linkuse as main transcript	c.4050+148C>T		intron_variant			NP_001305963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.4198C>T	p.Arg1400Ter	stop_gained	23/24	1	NM_004415.4	ENSP00000369129	P2	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.3582+616C>T		intron_variant		1		ENSP00000396591	A2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.4050+148C>T		intron_variant				ENSP00000518230	A2

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2024	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) -

Arrhythmogenic right ventricular dysplasia 8

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 26, 2018	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jan 17, 2023	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. -

Dilated cardiomyopathy 1A

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	Dec 26, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Feb 04, 2020	- -

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

Nov 07, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 09, 2018

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2023

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. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 03, 2021

- -

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

MutationTaster

Benign

1.0

A;N

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