rs397516974
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_004415.4(DSP):c.868G>A(p.Glu290Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
DSP
NM_004415.4 missense
NM_004415.4 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 9.86
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_004415.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.888
PP5
?
Variant 6-7565449-G-A is Pathogenic according to our data. Variant chr6-7565449-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44979.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.868G>A | p.Glu290Lys | missense_variant | 7/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.868G>A | p.Glu290Lys | missense_variant | 7/24 | ||
DSP | NM_001008844.3 | c.868G>A | p.Glu290Lys | missense_variant | 7/24 | ||
DSP | NM_001406591.1 | c.868G>A | p.Glu290Lys | missense_variant | 7/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.868G>A | p.Glu290Lys | missense_variant | 7/24 | 1 | NM_004415.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461852Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727230
GnomAD4 exome
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1
AN:
1461852
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31
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0
AN XY:
727230
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 08, 2023 | The p.E290K variant (also known as c.868G>A), located in coding exon 7 of the DSP gene, results from a G to A substitution at nucleotide position 868. The glutamic acid at codon 290 is replaced by lysine, an amino acid with similar properties. This variant has been detected in an individual with arrhythmogenic right ventricular cardiomyopathy (ARVC) and occurred de novo in an individual with dilated cardiomyopathy (Castelletti S et al. Int. J. Cardiol., 2017 Dec;249:268-273; Franaszczyk M et al. J Clin Med. 2020 Jan;9(2)). This variant has also been detected in a dilated cardiomyopathy genetic testing cohort, and in a proband with myocarditis-related sudden death case and two family members with fibrotic changes in their left ventricles; however, additional cardiac variants were also detected (Campuzano O et al. J. Am. Coll. Cardiol., 2015 Dec;66:2913-2914; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 31, 2012 | Variant classified as Uncertain Significance - Favor Pathogenic. The Glu290Lys v ariant in DSP has not been reported in the literature, but has been identified i n 1 Caucasian individual with ARVC by our laboratory. This variant has not been identified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). This low frequency supports that this variant is disease-causing, but is insufficient to establish this with confidence. Computational analyses (biochemical amino ac id properties, conservation, AlignGVGD, PolyPhen2, and SIFT) also suggest that t he Glu290Lys variant may impact the protein, though this information is not pred ictive enough to determine pathogenicity. Although this information supports th at the Glu290Lys variant may be pathogenic, additional studies are needed to ful ly assess its clinical significance. - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 290 of the DSP protein (p.Glu290Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy and/or dilated cardiomyopathy (PMID: 27532257, 32013205). ClinVar contains an entry for this variant (Variation ID: 44979). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Gain of ubiquitination at E290 (P = 0.0114);Gain of ubiquitination at E290 (P = 0.0114);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at