rs191564916
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The ENST00000261590.13(DSG2):c.1003A>G(p.Thr335Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000694 in 1,614,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T335T) has been classified as Benign.
Frequency
Genomes: 𝑓 0.00057 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00071 ( 0 hom. )
Consequence
DSG2
ENST00000261590.13 missense
ENST00000261590.13 missense
Scores
1
5
13
Clinical Significance
Conservation
PhyloP100: 6.66
Genes affected
DSG2 (HGNC:3049): (desmoglein 2) This gene encodes a member of the desmoglein family and cadherin cell adhesion molecule superfamily of proteins. Desmogleins are calcium-binding transmembrane glycoprotein components of desmosomes, cell-cell junctions between epithelial, myocardial, and other cell types. The encoded preproprotein is proteolytically processed to generate the mature glycoprotein. This gene is present in a gene cluster with other desmoglein gene family members on chromosome 18. Mutations in this gene have been associated with arrhythmogenic right ventricular dysplasia, familial, 10. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.20902443).
BS2
High AC in GnomAd4 at 87 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DSG2 | NM_001943.5 | c.1003A>G | p.Thr335Ala | missense_variant | 8/15 | ENST00000261590.13 | NP_001934.2 | |
| DSG2 | XM_047437315.1 | c.469A>G | p.Thr157Ala | missense_variant | 9/16 | XP_047293271.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DSG2 | ENST00000261590.13 | c.1003A>G | p.Thr335Ala | missense_variant | 8/15 | 1 | NM_001943.5 | ENSP00000261590 | P1 | |
| DSG2 | ENST00000682087.2 | n.834A>G | non_coding_transcript_exon_variant | 6/6 | ||||||
| DSG2 | ENST00000683614.2 | n.834A>G | non_coding_transcript_exon_variant | 6/7 |
Frequencies
GnomAD3 genomes 0.000571 AC: 87AN: 152240Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000521 AC: 130AN: 249422Hom.: 0 AF XY: 0.000502 AC XY: 68AN XY: 135326
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GnomAD4 exome AF: 0.000707 AC: 1034AN: 1461810Hom.: 0 Cov.: 35 AF XY: 0.000707 AC XY: 514AN XY: 727208
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GnomAD4 genome 0.000571 AC: 87AN: 152356Hom.: 0 Cov.: 33 AF XY: 0.000456 AC XY: 34AN XY: 74506
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:14Benign:5Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 10 Pathogenic:1Uncertain:4Other:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Sep 07, 2019 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,PP5,BP5. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 06, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Uncertain significance and reported on 01-22-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
| Likely pathogenic, flagged submission | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Loss of function and gain of function are reported mechanisms of disease in this gene and are associated with arrhythmogenic right ventricular dysplasia 10 (ARVD; MIM#610193) and dilated cardiomyopathy 1BB (DCM; MIM#612877) (ClinVar, PMID: 23071725). (I) 0108 - This gene is associated with both recessive and dominant disease. It is commonly associated to dominant inheritance, however recessive inheritance has been reported in severe DCM patients (OMIM). (I) 0112 - The ARVD condition associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to alanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2+v3) (218 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated cadherin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported in homozygous and heterozygous individuals with and without ARVD. It has also been reported as likely benign and VUS (ClinVar, LOVD, VCGS Cardiac db, PMID: 28818065, PMID: 33652588, PMID: 23381804, PMID: 35300203). (I) 0906 - Segregation evidence for this variant is inconclusive. This variant was found not to segregate in two families (PMID: 26230511, PMID: 34317382). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2024 | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 335 of the DSG2 protein (p.Thr335Ala). This variant is present in population databases (rs191564916, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy (PMID: 20031617, 20152563, 20864495, 21606390, 21636032, 23381804, 23871674, 24704780, 25445213, 28818065, 30790397). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 44278). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSG2 protein function with a negative predictive value of 95%. 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. - |
not provided Uncertain:5
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 27, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2024 | Reported in multiple heterozygous individuals in association with ARVD/C, dilated cardiomyopathy (DCM), Brugada syndrome and sudden unexplained death (PMID: 20031617, 20864495, 21553091, 21636032, 21606390, 21859740, 23381804, 24503780, 25445213, 26230511, 27194543, 27930701); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26230511, 23871885, 33968641, 33232181, 33673806, 33652588, 32917565, 33919104, 23861362, 23299917, 24585727, 20864495, 20857253, 20152563, 21859740, 21553091, 21606396, 21636032, 23810894, 24503780, 24704780, 21606390, 27194543, 25445213, 27930701, 28341588, 28818065, 30790397, 29802319, 29606362, 31712859, 31737537, 31402444, Bueno-Beti2022, 35061126, 28255936, 23871674, 32746448, 34758253, 35653365, 35712781, 36139162, 20031617, 36175056, 23381804) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 12, 2014 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 18, 2017 | One variant of uncertain clinical significance, c.1003A>G; p.Thr335Ala, was detected in the DSG2 gene by massively parallel sequencing and confirmed by Sanger sequencing. The c.1003A>G; p.Thr335Ala has been reported in patients with Arrhythmogenic right ventricular cardiomyopathy (ARVC) (Rasmussen et al. 2013, Christensen et al. 2010, den Haan et al. 2009, te Riele et al. 2013). Rasmussen (2013) observed homozygous brothers with ARVC who had unaffected heterozygote siblings and parents. Additionally, three heterozygote males with ARVC were reported in the same study with unaffected heterozygote parents. den Haan (2009) observed this variant in one heterozygote male with ARVC who also carried a loss of function variant in the PKP2 gene. This variant has also been reported in three patients with dilated cardiomyopathy (DCM) however with lack of segregation in the families (Garcia-Pavia et al. 2011, Pugh et al. 2014). Ng (2013) observed this variant with an allele frequency of 0.2 percent (on 3 out of 1,738 chromosomes) in individuals not selected for arrhythmia, cardiomyopathy, or a family history of sudden death and classified this variant likely benign. Rasmussen (2013) also demonstrated no significant changes in abundance or localization of the variant DSG2 protein by immuno-histochemical staining of myocardial or epidermal tissues. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.1 percent in the European Finnish population (identified on 29 out of 25,792 chromosomes), and is reported to the ClinVar database as a variant of uncertain significance (Variation ID: 44278). Given the overabundance of this variant in the control populations (from gnomAD) and, the reported cases of heterozygote patients and unaffected relatives with ARVC and DCM, it remains to be determined whether the p.Thr335Ala is a benign polymorphism or a pathogenic variant with low penetrance. - |
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1Uncertain:1Benign:1
| Likely pathogenic, flagged submission | clinical testing | Blueprint Genetics | Dec 07, 2015 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Dec 05, 2024 | assumed homozygous in two cases (one w cardiomyopathy, one w muscle weakness) - |
| Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
not specified Uncertain:2Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jul 05, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 31, 2023 | Variant summary: DSG2 c.1003A>G (p.Thr335Ala) results in a non-conservative amino acid change located in the Cadherin like domain (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 254132 control chromosomes (no homozygotes; gnomAD). The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00025), suggesting that the variant may be benign. c.1003A>G has been reported in the literature in multiple heterozygous individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (e.g., denHaan_2009, Xu_2010, Christensen_2010, Tan_2010, Cox_2011, Garcia-Pavia_2011, Quarta_2011, Rasmussen_2013, teRiele_2013, Iglesias_2021, Hathaway_2021), however without strong evidence for causality (e.g., lack of co-segregation data, lack of segregation with disease in some families, or co-occurrence with pathogenic variants in other ARVC-associated genes). However, the variant has also been reported in the homozygous state in several ARVC patients (e.g., Groeneweg_2013, Rasmussen_2013, Hermida_2019, Qadri_2017), and the variant was shown to segregate with disease and displayed complete penetrance in an autosomal recessive inheritance pattern in five homozygotes from one family (Qadri_2017). These reports do not provide unequivocal conclusions about association of the variant with autosomal dominant Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, but suggest the variant may be associated with recessive disease. Several co-occurrences with other pathogenic variants have been reported in heterozygous individuals in the literature and observed in our own laboratory (ARVD, PKP2 c.145_148delCAGA, p.Thr50fs; PKP2 c.235C>T, p.Arg79* in the literature; LQT1, KCNQ1 c.1075C>T, p.Q359* via internal testing), providing supporting evidence for a benign role. At least one publication reporting experimental evidence evaluating an impact on protein function was ascertained, however, it does not allow convincing conclusions about the variant effect while reporting that the altered protein was expressed and incorporated into desmosomes (e.g., Rasmussen_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23299917, 20864495, 21606396, 21859740, 23871674, 33673806, 30790397, 33919104, 23861362, 28818065, 21606390, 23381804, 20857253, 20152563, 20031617, 23810894). Sixteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n = 11; likely benign, n = 2; likely pathogenic, n = 2), and some cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 14, 2022 | The p.Thr335Ala variant in DSG2 has been classified as likely benign because it has been identified in 0.09% (23/25034) of Finnish and 0.07% (92/128596) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is larger than maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). Additionally, computational prediction tools and conservation analysis suggest that the p.Thr335Ala variant may not impact the protein, ACMG/AMP Criteria applied: BS1, BP4. - |
Cardiomyopathy Uncertain:1Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 24, 2019 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Mar 22, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 15, 2023 | - - |
Arrhythmogenic right ventricular dysplasia 10;C2752072:Dilated cardiomyopathy 1BB Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | DSG2 NM_001943.4 exon 8 p.Thr335Ala (c.1003A>G): This variant has been reported in the literature in multiple individuals with ARVC in the heterozygous state (den Haan 2009 PMID:20031617, Christensen 2010 PMID:20864495, Xu 2010 PMID:20152563, Kapplinger 2011 PMID:21636032, te Riele 2013 PMID:23810894, Green 2015 PMID:25445213, Medeiros-Domingo 2017 PMID:27194543) as well as at least 2 individuals with ARVC in the homozygous state, segregating with disease in 4 affected family members (Rasmussen 2013 PMID:23381804, Rasmussen 2014 PMID:24704780, Qadri 2017 PMID:28818065). Of note, the literature states that all heterozygous carrier relatives of these homozygous probands are unaffected. This variant has also been identified in 2 individuals with DCM, segregating with disease in 1 affected family member (Garcia-Pavia 2011 PMID:21859740, Pugh 2014 PMID:24503780). This variant is present in 0.1% (29/25792) Finnish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs191564916) and is present in ClinVar (Variation ID:44278). Evolutionary conservation and computational predictive tools for this variant are unclear. In vitro functional studies suggest that this variant may impact the protein (Rasmussen 2013 PMID:23381804). However, these studies may not accurately represent in vivo biological function. Due to contradictory evidence, the clinical significance of this variant is uncertain. - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 10, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
Calibrated prediction
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AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
N
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
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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