6-7555815-C-T

Position:

chr6-7555815-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_004415.4(DSP):c.268C>T(p.Gln90*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000124 in 1,613,730 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DSP
NM_004415.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.84

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:

DSP (HGNC:):

DSP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 6-7555815-C-T is Pathogenic according to our data. Variant chr6-7555815-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265102.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 linkuse as main transcript	c.268C>T	p.Gln90*	stop_gained	2/24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 linkuse as main transcript	c.268C>T	p.Gln90*	stop_gained	2/24		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 linkuse as main transcript	c.268C>T	p.Gln90*	stop_gained	2/24		NP_001008844.1	P15924-2B4DKX6Q4LE79
DSP	NM_001406591.1 linkuse as main transcript	c.268C>T	p.Gln90*	stop_gained	2/11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.268C>T	p.Gln90*	stop_gained	2/24	1	NM_004415.4	ENSP00000369129.3		P15924-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152274

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250568

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135480

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:

6.84e-7

AC:

AN:

1461456

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727034

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 25, 2024	PM2, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2025	Identified in individuals with cardiomyopathy and/or arrhythmia referred for genetic testing at GeneDx and in the published literature (PMID: 32372669); 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; This variant is associated with the following publications: (PMID: 30217213, 31402444, 36136372, 29181379, 31847883, 32372669) -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 05, 2018

The p.Gln90Ter variant is predicted to result in a truncated or absent protein product. This variant has not been reported in the medical literature; however a similar truncating variant (p.Q51Ter) was reported in one individual with Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD), whereby electrical abnormalities on electrocardiography and Holter monitoring were proposed as an indicator for high risk patients (te Riele, 2013). This variant is listed in the Genome Aggregation Database (gnomAD) identified on a single chromosome out of 245,444, and has been reported to the ClinVar database as a pathogenic/likely pathogenic variant (Variation ID: 265102). Based on these observations, the p.Gln90Ter variant is considered to be pathogenic. -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Apr 25, 2024

This variant changes 1 nucleotide in exon 2 of the DSP gene and is expected to introduce a premature translation stop signal at codon 90. The mutant transcript may undergo nonsense-mediated mRNA decay, resulting in an absent or non-functional protein product. There are multiple in-frame methionines in exon 3 prior to a known functional domain, and it is unknown if any of these methionines may serve as alternate translation initiation site, thereby potentially mitigating the effect of this p.Gln90* variant. This variant has been reported in a family affected with dilated cardiomyopathy or arrhythmogenic cardiomyopathy (PMID: 32372669), in two individuals affected with sudden death (PMID: 29181379, 31847883). This variant has been identified in 1/250568 chromosomes 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 Likely 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

Jan 03, 2024

This sequence change creates a premature translational stop signal (p.Gln90*) 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 (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with DSP-related conditions (PMID: 32372669). ClinVar contains an entry for this variant (Variation ID: 265102). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2024

The p.Q90* pathogenic mutation (also known as c.268C>T), located in coding exon 2 of the DSP gene, results from a C to T substitution at nucleotide position 268. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This variant was detected in a sudden death case for which autopsy findings showed evidence of cardiomyopathy (Rueda M et al. Front Cardiovasc Med, 2017 Nov;4:72). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Uncertain

0.95

Vest4

0.89

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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