rs191564916

chr18-31524877-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001943.5(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 NM_001943.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:12 B:5 O:1
• 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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20902443).
• BS2: High AC in GnomAd at 87 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSG2	NM_001943.5	c.1003A>G	p.Thr335Ala	missense_variant	8/15	ENST00000261590.13
DSG2	XM_047437315.1	c.469A>G	p.Thr157Ala	missense_variant	9/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSG2	ENST00000261590.13	c.1003A>G	p.Thr335Ala	missense_variant	8/15	1	NM_001943.5	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 AF: 0.000571 AC: 87 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000521 AC: 130 AN: 249422 Hom.: 0 AF XY: 0.000502 AC XY: 68 AN XY: 135326

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000974

Gnomad NFE exome AF: 0.000742

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000707 AC: 1034 AN: 1461810 Hom.: 0 Cov.: 35 AF XY: 0.000707 AC XY: 514 AN XY: 727208

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00112

Gnomad4 NFE exome AF: 0.000820

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000456 AC XY: 34 AN XY: 74506

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000731 Hom.: 1

Bravo AF: 0.000631

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000610 AC: 5

ExAC AF: 0.000555 AC: 67

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:12 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
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	GeneDx	Apr 04, 2023	Reported in multiple heterozygous individuals in association with ARVD/C, dilated cardiomyopathy (DCM), Brugada syndrome and sudden unexplained death (den Haan et al., 2009; Christensen et al., 2010; Campian et al., 2011; Kapplinger et al., 2011; Quarta et al., 2011; Garcia-Pavia et al., 2011; Rasmussen et al., 2013; Pugh et al., 2014; Green et al., 2015; Allegue et al., 2015; Medeiros- Domingos et al., 2016; Sanchez et al., 2016); 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, 20031617, 23381804, 34758253, 35653365, 35712781, 36139162) -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 27, 2021	- -

Arrhythmogenic right ventricular dysplasia 10 Pathogenic:1 Uncertain:3 Other:1

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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, 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. -
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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

not specified Uncertain:2 Benign:1

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 05, 2017	- -

Cardiomyopathy Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 24, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 15, 2023	- -
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	- -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1 Benign:1

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely pathogenic, flagged submission	clinical testing	Blueprint Genetics	Dec 07, 2015	- -

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

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.52	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.21
Sift	Uncertain	0.028	D
Sift4G	Benign	0.16	T
Polyphen		0.94	P
Vest4		0.51
MVP		0.75
MPC		0.37
ClinPred		0.059	T
GERP RS		4.0
Varity_R		0.57
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs191564916; hg19: chr18-29104840; COSMIC: COSV99079338; COSMIC: COSV99079338;