rs121913008

chr18-31519858-G-Achr18-31519858-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_001943.5(DSG2):c.137G>A(p.Arg46Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,972 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R46W) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 6.62

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 Pathogenic. Variant got 16 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, 13 uncertain in NM_001943.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31519857-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 863095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 18-31519858-G-A is Pathogenic according to our data. Variant chr18-31519858-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31519858-G-A is described in Lovd as [Pathogenic]. Variant chr18-31519858-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSG2	NM_001943.5	c.137G>A	p.Arg46Gln	missense_variant	3/15	ENST00000261590.13
DSG2	XM_047437315.1	c.-398G>A		5_prime_UTR_variant	4/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSG2	ENST00000261590.13	c.137G>A	p.Arg46Gln	missense_variant	3/15	1	NM_001943.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74288

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 06, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. We classify this variant as likely disease causing. This variant has been reported in 6 unrelated individuals with ARVC (7 total, though two shared a haplotype) (Awad et al 2006, Bhuiyan et al 2009 and Fressart et al 2010). There is minimal segregation data on the variant. Awad et al (2006) first reported the variant (as p.Arg45Gln) in an individual with ARVC. The proband’s mother had this variant and was thought to be an obligate carrier as her father’s history was suspicious for ARVC. While this study did not include analysis of other ARVC genes, the same group later reported on evaluated of 5 genes in their cohort, including the individuals originally reported in the 2006 paper (den Haan et al 2009). From that paper it seems that this patient had only the one desmosomal variant, though it isn’t completely clear that the individual with this variant reported by Awad et al is the same as the individual reported by den Haan et al. Bhuiyan et al (2009) reported the variant in two unrelated individuals in their Dutch cohort who had the same haplotype. These patients did not have any variants in PKP2 or DSC2. Fressart et al (2010) reported three unrelated ARVC patients with this variant. Two of these patients had no other variants in JUP, DSP, PKP2, DSG2, and DSC2. The third patient also had a missense variant in PKP2 (p.Arg811Ser) that was absent in the 300 controls reported in the paper but is present in one of ~2500 individuals in the NHLBI Exome dataset. Quarta et al (2011) reported observing the variant in their British sample (few details provided). This is a semi conservative amino acid change with a basic Arginine replaced with a neutral Glutamine. Argninie is highly conserved at this amino acid position across species. Awad et al (2006) reported that this variant affects a residue that is a recognition site for cleavage of the protein precursor, suggesting that the variant will impede production of a mature protein product. Gaertner et al (2012) expressed the extracellular cadherin domain of the desmoglein 2 protein with p.Arg46Gln and found that the variant destroyed a prodomain cleavage site leading to failed cleavage in vitro. They also observed increased cellular adhesion. In silico analysis with PolyPhen predicts the amino acid change to be probably damaging to protein structure/function. Other missense variants at or near this codon have been reported in ARVC cases and are not present in the current NHLBI Exome dataset (Nov 2011, ~2500 individuals): p.Arg46Trp (Fressart et al 2010), p.Arg49His (Fressart et al 2010, Awad et al 2006, den Haan et al 2009, Barahona-Dussault et al 2010). In total this variant has not been seen in 7,850 published controls, laboratory controls, and publicly available general population samples. Across all publications it has not been observed in over 1150 presumably healthy controls. p.Arg46Gln is not listed in1000 Genomes (http://browser.1000genomes.org/index.htm) (as of 2/6/14). It is listed in dbSNP, but that points to the OMIM entry for the variant seen in patients with ARVC. There is no variation at codon 46 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 2/6/14). -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2021	Reported in ClinVar as pathogenic (ClinVar Variant ID#16812; ClinVar); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution has been shown to impair prodomain cleavage and occurs at a position that is conserved across species (Gaertner et al., 2012); This variant is associated with the following publications: (PMID: 28097316, 23911551, 20857253, 23137101, 26688388, 24967631, 21606396, 16773573, 20400443, 21606390, 20031616, 20031617, 29343803, 31542937, 31386562, 31402444, 30790397, 33019804, 31845994, 23071725, 23381804, 26582918) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Arrhythmogenic right ventricular dysplasia 10 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Feb 05, 2019	This c.137G>A (p.Arg46Gln) variant in the DSG2 gene is reported in multiple probands affected with arrhythmogenic right ventricular dysplasia/cardiomyopathy (PMID 16773573, 20031616, 20031617, 20400443, 21606390, 21606396, 23381804) and segregates with disease in some of the families (PMID 23071725, 23381804). Functional studies showed this is a potential gain-of-function variant which produces a mutant protein product with extended N-terminus (PMID 23381804). In addition, this variant is predicted to be damaging by multiple in silico algorithms. Therefore, the c.137G>A (p.Arg46Gln) variant in the DSG2 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Dec 16, 2020	ACMG codes:PS3,PS4M,PM2,PP3,PP5, -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 12, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 46 of the DSG2 protein (p.Arg46Gln). This variant is present in population databases (rs121913008, gnomAD 0.004%). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 16773573, 23381804, 30790397, 31542937). It has also been observed to segregate with disease in related individuals. This variant is also known as 134G>A (R45Q). ClinVar contains an entry for this variant (Variation ID: 16812). 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) has been performed at Invitae 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. Experimental studies have shown that this missense change affects DSG2 function (PMID: 23071725). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2006	- -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 29, 2022	This missense variant replaces arginine with glutamine at codon 46 in the propeptide sequence domain of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Studies with tissue samples from carrier individuals and transfected cell lines have shown that this variant prevents the cleavage of the N-terminal propeptide that is required for normal protein maturation (PMID: 23071725, 23381804, 31845994). This variant has been reported in over ten unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 23381804, 30790397, 31542937, 31386562, 32268277, 33821670, 23381804, 31542937). It has been shown that this variant segregates with disease in at least six families (PMID: 23381804, 31542937). This variant has been identified in 1/280866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 30, 2019	- -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 01, 2017	proposed classification - variant undergoing re-assessment, contact laboratory -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 08, 2023	This missense variant replaces arginine with glutamine at codon 46 in the propeptide sequence domain of the DSG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Studies with tissue samples from carrier individuals and transfected cell lines have shown that this variant prevents the cleavage of the N-terminal propeptide that is required for normal protein maturation (PMID: 23071725, 23381804, 31845994). This variant has been reported in over ten unrelated individuals affected with arrhythmogenic cardiomyopathy (PMID: 23381804, 30790397, 31542937, 31386562, 32268277, 33821670, 23381804, 31542937). It has been shown that this variant segregates with disease in at least six families (PMID: 23381804, 31542937). This variant has been identified in 1/280866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Arrhythmogenic right ventricular dysplasia 10;C2752072:Dilated cardiomyopathy 1BB Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 20, 2021

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2021

The p.R46Q pathogenic mutation (also known as c.137G>A), located in coding exon 3 of the DSG2 gene, results from a G to A substitution at nucleotide position 137. The arginine at codon 46 is replaced by glutamine, an amino acid with highly similar properties. This variant (also described as legacy p.R45Q, c.134G>A) has been reported in multiple individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC), and co-segregation with disease has been reported in several families (Awad MM et al. Am J Hum Genet, 2006 Jul;79:136-42; Bhuiyan ZA et al. Circ Cardiovasc Genet, 2009 Oct;2:418-27; Rasmussen TB et al. Hum Mutat, 2013 May;34:697-705; Broendberg AK et al. Eur J Hum Genet, 2018 03;26:303-313; Kerkar A et al. Circ Genom Precis Med, 2019 10;12:452-454). This alteration is located in a highly conserved recognition motif (RQKR) for the endoproteolytic cleavage of an NH2-terminal propeptide sequence, required for activation of the desmoglein protein (Posthaus H et al. FEBS Lett, 2003 Feb;536:203-8). Studies have suggested disruption of this site may prevent proper post-translational processing, and have demonstrated the immature protein may still localize and incorporate into desmosomal junctions despite the N-terminal extension, although the exact physiological implications are not yet clear (Awad MM et al. Am J Hum Genet, 2006 Jul;79:136-42; Gaertner A et al. PLoS One, 2012 Oct;7:e47097; Rasmussen 2013 Hum Mutat 2013 May;34(5):697-705; Vite A et al. Europace, 2020 02;22:320-329). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	30
Dann	Benign	0.97
DEOGEN2	Uncertain	0.76	D;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	0.10	A;A
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.63
MutPred		0.94		Loss of MoRF binding (P = 0.0119);Loss of MoRF binding (P = 0.0119);
MVP		0.91
MPC		0.45
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs121913008; hg19: chr18-29099821;