rs191564916
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_001943.5(DSG2):โc.1003A>Gโ(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
Consequence
NM_001943.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DSG2 | ENST00000261590.13 | c.1003A>G | p.Thr335Ala | missense_variant | Exon 8 of 15 | 1 | NM_001943.5 | ENSP00000261590.8 | ||
| DSG2 | ENST00000682087.2 | n.834A>G | non_coding_transcript_exon_variant | Exon 6 of 6 | ||||||
| DSG2 | ENST00000683614.2 | n.834A>G | non_coding_transcript_exon_variant | Exon 6 of 7 |
Frequencies
GnomAD3 genomes 0.000571 AC: 87AN: 152240Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000521 AC: 130AN: 249422Hom.: 0 AF XY: 0.000502 AC XY: 68AN XY: 135326
GnomAD4 exome AF: 0.000707 AC: 1034AN: 1461810Hom.: 0 Cov.: 35 AF XY: 0.000707 AC XY: 514AN XY: 727208
GnomAD4 genome 0.000571 AC: 87AN: 152356Hom.: 0 Cov.: 33 AF XY: 0.000456 AC XY: 34AN XY: 74506
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular dysplasia 10 Pathogenic:1Uncertain:4Other:1
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. -
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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSG2 protein function. 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. -
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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. -
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 -
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. -
not provided Uncertain:5
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) -
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The DSG2 c.1003A>G; p.Thr335Ala variant (rs191564916, ClinVar Variation ID: 44278) is reported in the literature in homozygous and heterozygous individuals and families affected with arrhythmogenic cardiomyopathy (Bueno-Beti 2022, Christensen 2022, Costa 2021, den Haan 2009, Hermida 2019, Mast 2019, Qadri 2017, Rasmussen 2013, Robles-Mezcua 2023). Additionally, this variant is found in individuals affected with dilated cardiomyopathy, sudden cardiac death, and other cardiomyopathies (Ammirati 2022, Burstein 2021, Christensen 2010, Garcia-Pavia 2011). However, this variant has also been observed in unaffected heterozygous carriers (Garcia-Pavia 2011, Qadri 2017, Rasmussen 2013). This variant is found in the general population with an overall allele frequency of 0.05% (146/280,830 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.206). Immuno-histochemical staining of myocardial, epidermal, or buccal tissues demonstrate no significant changes in abundance or localization of the variant DSG2 protein (Rasmussen 2013, Bueno-Beti 2022). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Ammirati E et al. Acute Myocarditis Associated With Desmosomal Gene Variants. JACC Heart Fail. 2022 Oct;10(10):714-727. PMID: 36175056. Bueno-Beti C et al. Analysis of buccal mucosa as a prognostic tool in children with arrhythmogenic cardiomyopathy. Prog Pediatr Cardiol. 2022 Mar;64:None. PMID: 35300203. Burstein DS et al. Genetic variant burden and adverse outcomes in pediatric cardiomyopathy. Pediatr Res. 2021 May;89(6):1470-1476. PMID: 32746448. Christensen et al. Wide spectrum of desmosomal mutations in Danish patients with arrhythmogenic right ventricular cardiomyopathy. J Med Genet. 2010 Nov;47(11):736-44. PMID: 20864495. Christensen AH et al. Genotype-phenotype correlation in arrhythmogenic right ventricular cardiomyopathy-risk of arrhythmias and heart failure. J Med Genet. 2022 Sep;59(9):858-864. PMID: 34400560. Costa S et al. Impact of Genetic Variant Reassessment on the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy Based on the 2010 Task Force Criteria. Circ Genom Precis Med. 2021 Feb;14(1):e003047. PMID: 33232181. den Haan et al. Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Cardiovasc Genet. 2009 Oct;2(5):428-35. PMID: 20031617. Garcia-Pavia et al. Desmosomal protein gene mutations in patients with idiopathic dilated cardiomyopathy undergoing cardiac transplantation: a clinicopathological study. Heart. 2011 Nov;97(21):1744-52. PMID: 21859740. Hermida A et al. High risk of heart failure associated with desmoglein-2 mutations compared to plakophilin-2 mutations in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Eur J Heart Fail. 2019 Jun;21(6):792-800. PMID: 30790397. Mast TP et al. Prolonged Electromechanical Interval Unmasks Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy in the Subclinical Stage. J Cardiovasc Electrophysiol. 2016 Mar;27(3):303-14. PMID: 26585103. Qadri S et al. Case reports of two pedigrees with recessive arrhythmogenic right ventricular cardiomyopathy associated with homozygous Thr335Ala variant in DSG2. BMC Med Genet. 2017 Aug 17;18(1):86. PMID: 28818065. Rasmussen et al. Mutated desmoglein-2 proteins are incorporated into desmosomes and exhibit dominant-negative effects in arrhythmogenic right ventricular cardiomyopathy. Hum Mutat. 2013 May;34(5):697-705. PMID: 23381804. Robles-Mezcua A et al. The Novel Variant NP_00454563.2 (p.Glu259Glyfs*77) in Gene PKP2 Associated with Arrhythmogenic Cardiomyopathy in 8 Families from Malaga, Spain. Genes (Basel). 2023 Jul 19;14(7):1468. PMID: 37510372. -
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1Uncertain:1Benign:1
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assumed homozygous in two cases (one w cardiomyopathy, one w muscle weakness) -
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not specified Uncertain:2Benign:1
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. -
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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. -
Cardiomyopathy Uncertain:1Benign:2
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Arrhythmogenic right ventricular dysplasia 10;C2752072:Dilated cardiomyopathy 1BB Uncertain:1
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
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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at