rs121913006

chr18-31519867-G-Achr18-31519867-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.146G>A(p.Arg49His) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,876 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. R49C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DSG2 NM_001943.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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 2 benign, 14 uncertain in NM_001943.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31519866-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 18-31519867-G-A is Pathogenic according to our data. Variant chr18-31519867-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-31519867-G-A is described in Lovd as [Pathogenic]. Variant chr18-31519867-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.146G>A	p.Arg49His	missense_variant	3/15	ENST00000261590.13
DSG2	XM_047437315.1	c.-389G>A		5_prime_UTR_variant	4/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSG2	ENST00000261590.13	c.146G>A	p.Arg49His	missense_variant	3/15	1	NM_001943.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249482 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135358

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727240

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: 0.00000719

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000454 Hom.: 0

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 10 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 17, 2023	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. ClinVar contains an entry for this variant (Variation ID: 16810). This variant is also known as R48H. This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 19151369, 19863551, 20400443). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs121913006, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 49 of the DSG2 protein (p.Arg49His). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 06, 2017	This c.146G>A (p.Arg49His) variant in the DSG2 gene has previously been reported in a 41 y/o patient with ARVD cardiomyopathy [PMID 19151369]. Both parents were negative for the change, suggesting that this variant arises de novo in the patient. This variant was also reported in a 42 y/o patient with ARVD cardiomyopathy (reported as p.Arg48His in PMID 16773573]. The patient was compound heterozygous for p.Trp305* and p.Arg48His. The trp305* was inherited from the asymptomatic mother and also present in one sibling, also asymptomatic. The father was not available for testing. The variant is located in the propeptide domain, in the furin cleavage site and is hypothesized to disrupt the production of the mature protein. This variant has been observed in one heterozygous individual from the ExAC database (http://exac.broadinstitute.org/variant/18-29099830-G-A). Arginine at position 49 of the DSG2 protein is highly conserved. While not clinically validated, computer-based algorithms SIFT and Polyphen2 predict this p.Arg49His change to be deleterious. It is thus interpreted as a pathogenic variant. -

Arrhythmogenic right ventricular cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 11, 2023	This c.146G>A (p.Arg49His) variant in the DSG2 gene has previously been reported in a 41 y/o patient with ARVD/cardiomyopathy [PMID 19151369]. Both parents were negative for the change, suggesting that this variant arises de novo in the patient. This variant was also reported in a 42 y/o patient with ARVD/cardiomyopathy (reported as p.Arg48His in PMID 16773573]. The patient was compound heterozygous for p.Trp305* and p.Arg48His. The p.Trp305* was inherited from the asymptomatic mother and also present in one sibling, also asymptomatic. The father was not available for testing. The variant is located in the propeptide domain, in the furin cleavage site and is hypothesized to disrupt the production of the mature protein. This variant has been observed in one heterozygous individual from the ExAC database (http://exac.broadinstitute.org/variant/18-29099830-G-A). Arginine at position 49 of the DSG2 protein is highly conserved. While not clinically validated, computer-based algorithms SIFT and Polyphen2 predict this p.Arg49His change to be deleterious. It is thus interpreted as a pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 31, 2019	The p.Arg49His variant in DSG2 has been reported in > 10 individuals with clinical features of ARVC, including 1 de novo and 2 compound heterozygous occurrences (Awad 2006, den Haan 2009, Gandjbakhch 2009, Fressart 2010, Barahona-Dussault 2010, Tan 2010, Xu 2010, Gaido 2017, Walsh 2017). Additionally, the variant segregated with disease in 2 affected relatives from 1 family (Gaido, 2017). This variant has also been reported in ClinVar (Variation ID 16810) and has been identified in 1/113204 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that the p.Arg49His variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg49His variant is likely pathogenic. ACMG/ AMP Criteria applied: PS2, PM2, PS4_Moderate, PP3. -

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Jun 03, 2022

We observed a rare c.146G>A (p.R49H) genetic variant in the DSG2 gene in a 19-y.o. male proband, diagnosed with arrhythmogenic right ventricular cardiomyopathy (definite diagnosis). ClinVar contains an entry for this variant (Variation ID: 16810) observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 16773573‚ 19151369‚ 20152563‚ 20400443‚ 19863551‚ 20031617‚ 23671136‚ 28283360‚ 25820315‚ 20857253). Online bioinformatic resources classify the c.146G>A (p.R49H) variant as probably pathogenic. The p.R49H variant predicted to abolish a cleavage motif Arg-X-Lys-Arg (RXKR) in desmoglein, disrupting production of mature, functional protein (Awad et al., 2006). Functional studies show the c.146G>A (p.R49H) variant abolishes pro-peptide cleavage and affects desmosomal adhesiveness (Vite et al., 2020). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 17, 2020

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Functional studies show R49H abolishes pro-peptide cleavage and affects desmosomal adhesiveness (Vite et al., 2020); 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: 29237690, 23671136, 19151369, 20152563, 16773573, 20400443, 27532257, 28283360, 19863551, 25820315, 20031617, 20857253, 31447099, 31845994, 32268277, 31645976, 30790397, 32356610, 31402444) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	27
Dann	Uncertain	0.97
DEOGEN2	Uncertain	0.75	D;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	0.97	A;A
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.7	D;.
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.77
MutPred		0.94		Loss of MoRF binding (P = 0.0122);Loss of MoRF binding (P = 0.0122);
MVP		0.96
MPC		0.46
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.49
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121913006; hg19: chr18-29099830; COSMIC: COSV99852889;