rs780626687
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_004415.4(DSP):c.1067C>A(p.Thr356Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,860 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T356T) has been classified as Benign.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
DSP
NM_004415.4 missense
NM_004415.4 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 7.90
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 Uncertain_significance. Variant got 5 ACMG points.
PM1
In a repeat Spectrin 2 (size 103) in uniprot entity DESP_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_004415.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.769
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DSP | NM_004415.4 | c.1067C>A | p.Thr356Lys | missense_variant | 9/24 | ENST00000379802.8 | NP_004406.2 | |
| DSP | NM_001319034.2 | c.1067C>A | p.Thr356Lys | missense_variant | 9/24 | NP_001305963.1 | ||
| DSP | NM_001008844.3 | c.1067C>A | p.Thr356Lys | missense_variant | 9/24 | NP_001008844.1 | ||
| DSP | NM_001406591.1 | c.1067C>A | p.Thr356Lys | missense_variant | 9/11 | NP_001393520.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DSP | ENST00000379802.8 | c.1067C>A | p.Thr356Lys | missense_variant | 9/24 | 1 | NM_004415.4 | ENSP00000369129 | P2 | |
| DSP | ENST00000418664.2 | c.1067C>A | p.Thr356Lys | missense_variant | 9/24 | 1 | ENSP00000396591 | A2 | ||
| DSP | ENST00000710359.1 | c.1067C>A | p.Thr356Lys | missense_variant | 9/24 | ENSP00000518230 | A2 | |||
| DSP | ENST00000682228.1 | n.391C>A | non_coding_transcript_exon_variant | 3/3 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152102Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251198Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135760
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461758Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727182
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GnomAD4 genome 0.00000657 AC: 1AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74298
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 08, 2021 | Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 199858; Landrum et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25227139, 26399581, 27535533, Rawal2021[CaseReport]) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 09, 2016 | Variant summary: The c.1067C>A (p.Thr356Lys) in DSP gene is a missense change that involves a conserved nucleotide and 4/4 in silico tools predict deleterious outcome. The variant of interest is located in the spectrin repeat domain that is known to be involved in cytoskeletal structure. The variant is absent from control dataset of ExAC. This variant has been observed in 1 family with 2 affected siblings presented with dilated cardiomyopathy with severe left ventricular insufficiency, woolly hair and focal palmoplantar keratosis. Both pts carried the variant of interest in compound heterozygosity with maternally inherited c.2131_2132delAG, p.S711Cfs*4. Siblings father (an obligate carrier of the variant of interest, deceased) has suffered from a MI from young age. No functional studies determining the functional impact of this variant have been conducted and published at the time of evaluation. One reputable database/clinical laboratory classified this variant as VUS. Additional clinical and functional data are needed to classify this variant with confidence. Taking together, the variant was classified as VUS-Possibly Pathogenic until more information becomes available. - |
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces threonine with lysine at codon 356 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in compound heterozygosity with c.2131_2132delAG in two siblings affected with palmoplantar keratoderma, woolly hair and dilated cardiomyopathy (Carvajal syndrome), and the variant in question was inherited from the father who had myocardial infarction at a young age (PMID 25227139). This variant has been reported in another three individuals affected with DSP-related cardiomyopathy from two different families (PMID: 34352074, 36768812). This variant has also been observed in three asymptomatic individuals with imaging abnormalities involving left ventricle when screened with cardiac magnetic resonance, who were from a family with a history of arrhythmogenic ventricular cardiomyopathy and sudden cardiac death (PMID: 34317553). This variant has been identified in 1/251198 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 356 of the DSP protein (p.Thr356Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Carvajal syndrome and/or clinical features of arrhythmogenic cardiomyopathy (PMID: 25227139, 34352074). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 199858). 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. - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 03, 2023 | This missense variant replaces threonine with lysine at codon 356 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in compound heterozygosity with c.2131_2132delAG in two siblings affected with palmoplantar keratoderma, woolly hair and dilated cardiomyopathy (Carvajal syndrome), and the variant in question was inherited from the father who had myocardial infarction at a young age (PMID 25227139). This variant has been reported in another three individuals affected with DSP-related cardiomyopathy from two different families (PMID: 34352074, 36768812). This variant has also been observed in three asymptomatic individuals with imaging abnormalities involving left ventricle when screened with cardiac magnetic resonance, who were from a family with a history of arrhythmogenic ventricular cardiomyopathy and sudden cardiac death (PMID: 34317553). This variant has been identified in 1/251198 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Primary dilated cardiomyopathy Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 24, 2016 | - - |
Keratosis palmoplantaris striata 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Uncertain significance. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 17, 2022 | The p.T356K variant (also known as c.1067C>A), located in coding exon 9 of the DSP gene, results from a C to A substitution at nucleotide position 1067. The threonine at codon 356 is replaced by lysine, an amino acid with similar properties. This variant was reported in two compound heterozygous siblings with a maternally inherited DSP splicing variant, dilated cardiomyopathy, woolly or sparse hair, and mild palmoplantar keratosis (Pigors M et al. Acta Derm. Venereol., 2015 Mar;95:337-40). This alteration was also reported in family members of a proband who suffered sudden cardiac death and had features of arrhythmogenic right ventricular cardiomyopathy (ARVC) on autopsy; some of the family members who had genetic testing also carried a missense alteration in JUP (Rawal AS et al. JACC Case Rep, 2021 Mar;3:438-442). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
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 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 05, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
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
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Gain of ubiquitination at T356 (P = 0.0238);Gain of ubiquitination at T356 (P = 0.0238);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at