rs727505115

Positions:

• chr6-7572069-G-A
• chr6-7572069-G-C

Variant summary

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

The NM_004415.4(DSP):​c.2130+1G>A variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 splice_donor
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.88

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.3, offset of 4, new splice context is: tagGTatct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7572069-G-A is Pathogenic according to our data. Variant chr6-7572069-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7572069-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.2130+1G>A		splice_donor_variant		ENST00000379802.8	NP_004406.2
DSP	NM_001008844.3	c.2130+1G>A		splice_donor_variant			NP_001008844.1
DSP	NM_001319034.2	c.2130+1G>A		splice_donor_variant			NP_001305963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.2130+1G>A		splice_donor_variant		1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.2130+1G>A		splice_donor_variant		1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.2130+1G>A		splice_donor_variant				ENSP00000518230	A2
DSP	ENST00000684395.1	n.771+1G>A		splice_donor_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2024	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Different pathogenic variant affecting the same nucleotide (2130+1 G>C) was reported in a patient with biventricular dilation and premature ventricular contractions; variant segregated with disease in 3 affected relatives (PMID: 20716751); Not observed at significant frequency in large population cohorts (gnomAD); Identified in a patient who underwent genetic testing for arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 30847666); This variant is associated with the following publications: (PMID: 20716751, 30847666) -

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

Jul 11, 2023

The c.2130+1G>A variant of the DSP gene is predicted to affect mRNA splicing and result in an absent or disrupted protein product. Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). A similar variant (c.2130+1G>C) has been reported in 1 adult with biventricular dilation and PVCs and segregated with disease in 3 affected relatives (PMID: 20716751). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Therefore the c.2130+1G>A variant of the DSP gene is classified as likely pathogenic. -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

This sequence change affects a donor splice site in intron 15 of the DSP gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with DSP-related conditions (PMID: 27532257, 30847666). ClinVar contains an entry for this variant (Variation ID: 179772). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 21, 2023

This variant causes a G to A nucleotide substitution at the +1 position of intron 15 of the DSP gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Another variant at the same position, c.2130+1G>C (also known as IVS15+1G>C), has been observed in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257) and in another individual affected with idiopathic dilated cardiomyopathy (PMID: 20716751). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 08, 2014

The 2130+1G>A variant in DSP has not been previously reported in individuals wit h cardiomyopathy or in large population studies. This variant occurs in the inv ariant region (+/- 1,2) of the splice consensus sequence and is predicted to cau se altered splicing leading to an abnormal or absent protein. A similar variant (2130+1G>C) has been reported in 1 adult with biventricular dilation and PVCs an d segregated with disease in 3 affected relatives (Elliott 2010). In summary, al though additional studies are required to fully establish its clinical significa nce, the 2130+1G>A variant is likely pathogenic. -

DSP-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 09, 2023

The DSP c.2130+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in an individual with arrhythmogenic right ventricular cardiomyopathy (supplementary file 2 - van Lint et al. 2019. PubMed ID: 30847666). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in DSP are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.95		Position offset: 3
DS_DL_spliceai		0.93		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: rs727505115; hg19: chr6-7572302; COSMIC: COSV65795037;