rs121913006

Variant names:

• chr18-31519867-G-A
• rs121913006
• NM_001943.5:c.146G>A

Variant summary

Our verdict is Pathogenic. The variant received 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 Likely pathogenic.

• 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:8
• Conservation: PhyloP100: 6.62
• Publications: 27 publications found

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]

DSG2 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 10

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy 1BB

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 20 uncertain in NM_001943.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-31519866-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 450040.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 16810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSG2	NM_001943.5	c.146G>A	p.Arg49His	missense_variant	Exon 3 of 15	ENST00000261590.13	NP_001934.2
DSG2	XM_047437315.1	c.-389G>A		5_prime_UTR_variant	Exon 4 of 16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13	c.146G>A	p.Arg49His	missense_variant	Exon 3 of 15	1	NM_001943.5	ENSP00000261590.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249482 AF XY: 0.00000739

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112002

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000180 Hom.: 0

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 10 Pathogenic:3

Jun 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is present in population databases (rs121913006, gnomAD 0.0009%). 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 also known as R48H. ClinVar contains an entry for this variant (Variation ID: 16810). 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. For these reasons, this variant has been classified as Pathogenic. -

Jul 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 06, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 11, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 31, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 03, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 16, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies show R49H abolishes pro-peptide cleavage and affects desmosomal adhesiveness (PMID: 31845994); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29237690, 23671136, 20152563, 16773573, 20400443, 27532257, 28283360, 19863551, 25820315, 20031617, 20857253, 36175056, 36252119, 36264615, 31447099, 32268277, 31645976, 32356610, 31402444, 35819174, 30790397, 19151369, 31845994) -

Cardiovascular phenotype Pathogenic:1

Mar 05, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PS4_mod, PM1, PM2, PP1_mod, PS3_supp, PP3 -

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;.
PhyloP100		6.6
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
PromoterAI		0.019	Neutral
Varity_R		0.49
gMVP		0.93
Mutation Taster		=20/80	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121913006; hg19: chr18-29099830; COSMIC: COSV99852889;