rs200484060

Positions:

chr18-31536370-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_001943.5(DSG2):c.1592T>G(p.Phe531Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,614,182 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

DSG2
NM_001943.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:1

Conservation

PhyloP100: 6.16

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

BS2

High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSG2	NM_001943.5 linkuse as main transcript	c.1592T>G	p.Phe531Cys	missense_variant	11/15	ENST00000261590.13	NP_001934.2	Q14126
DSG2	XM_047437315.1 linkuse as main transcript	c.1058T>G	p.Phe353Cys	missense_variant	12/16		XP_047293271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSG2	ENST00000261590.13 linkuse as main transcript	c.1592T>G	p.Phe531Cys	missense_variant	11/15	1	NM_001943.5	ENSP00000261590.8		Q14126

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

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

GnomAD3 exomes

AF:

0.0000561

AC:

AN:

249384

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

135290

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000779

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000529

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000577

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000662

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 12, 2022	This missense variant replaces phenylalanine with cysteine at codon 531 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A study using a homozygous knock-in mouse model has reported that this variant results in a cardiomyopathy phenotype with left ventricular systolic dysfunction (Wang et. al, 2019). This variant has been reported in over ten individuals of East Asian ancestry affected with arrhythmogenic right ventricular cardiomyopathy, either in homozygous or compound heterozygous state (PMID: 18632414, 23514727, 24125834, 25765472, 28578331, 30129429, 30177324, 30454721, 31183845, 31645976; Wang et. al, 2019, https://doi.org/10.1093/eurheartj/ehz746.0202). In these families, over 20 heterozygous family members were reported to be unaffected, while several heterozygotes were reported to be affected with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, or sudden unexplained death. This variant has also been identified in 16/280790 chromosomes (16/19518 East Asian chromosomes, 0.0819%) in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in autosomal dominant arrhythmogenic cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 22, 2018	- -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Apr 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 11, 2024	This missense variant replaces phenylalanine with cysteine at codon 531 of the DSG2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A study using a homozygous knock-in mouse model has reported that this variant results in a cardiomyopathy phenotype with left ventricular systolic dysfunction (Wang et. al, 2019). This variant has been reported in over ten individuals of East Asian ancestry affected with arrhythmogenic right ventricular cardiomyopathy, either in homozygous or compound heterozygous state (PMID: 18632414, 23514727, 24125834, 25765472, 28578331, 30129429, 30177324, 30454721, 31183845, 31645976; Wang et. al, 2019, https://doi.org/10.1093/eurheartj/ehz746.0202). In these families, over 20 heterozygous family members were reported to be unaffected, while several heterozygotes were reported to be affected with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, or sudden unexplained death. This variant has also been identified in 16/280790 chromosomes (16/19518 East Asian chromosomes, 0.0819%) in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in autosomal dominant arrhythmogenic cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2024

The p.F531C variant (also known as c.1592T>G), located in coding exon 11 of the DSG2 gene, results from a T to G substitution at nucleotide position 1592. The phenylalanine at codon 531 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in the homozygous state in individuals of Asian background with arrhythmogenic right ventricular cardiomyopathy (ARVC) and segregated with disease in at least one family; however, when detected in the heterozygous state, additional cardiac variants were detected and/or clinical details were limited (Yu CC et al. J. Formos Med Assoc. 2008;107:548-58; Bao J et al. Circ Cardiovasc Genet. 2013;6:552-6; Ohno S et al. Circ J. 2013;77:1534-42; Zhou X et al. Eur J Med Genet. 2015;58(4):258-65; Lin Y et al. Cardiology. 2017;138:41-54; Zhang B et al. BMC Med. 2024 Sep 4;22(1):361). Heterozygous family members have been reported to be unaffected or to have only mild clinical features consistent with ARVC (Lin Y et al. J Electrocardiol , 2018 Jun;51:837-843; Chen L et al. Int. J. Cardiol., 2019 Jan;274:263-270; Chen X et al. Hum Genome Var, 2019 Aug;6:38). An in vivo knock-in mouse model showed affected mice in the homozygous state; however, heterozygous mice were unaffected (Zhang B et al. BMC Med. 2024 Sep 4;22(1):361). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Although evidence suggests that this alteration may be pathogenic when found in the homozygous state, supporting evidence for a role in autosomal dominant ARVC is limited. Based on the majority of available evidence to date, this variant is likely to be pathogenic in association with autosomal recessive ARVC; however, the clinical significance of this alteration with respect to autosomal dominant ARVC remains unclear. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 23, 2011

The Phe531Cys variant (DSG2) has been reported as a homozygous variant in one Ta wainese individual with ARVD and was absent in 200 control chromosomes (Yu 2008) . Phenylalanine (Phe) at position 531 is highly conserved across evolutionarily distant species, increasing the likelihood that a change would not be tolerated. Computational tools are mixed on the predicted impact to the protein (PolyPhen 2 & SIFT = pathogenic, AlignGVGD = benign), though the accuracy of these tools i s unknown. In summary, the clinical significance of this variant cannot be deter mined at this time. -

Arrhythmogenic right ventricular dysplasia 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 531 of the DSG2 protein (p.Phe531Cys). This variant is present in population databases (rs200484060, gnomAD 0.08%), 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 (PMID: 18632414, 23514727, 24238504, 25765472, 28578331, 28878402, 30454721, 30830208, 31645976). ClinVar contains an entry for this variant (Variation ID: 44283). 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. 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2018

The F531C variant of uncertain significance in the DSG2 gene has been previously reported in either the heterozygous or homozygous state in several Asian individuals with definite or suspected ARVC (Yu et al., 2008; Bao et al., 2013a; Bao et al., 2013b; Ohno et al., 2013); however, detailed clinical information and segregation data were not provided for most probands. In addition, one of these probands, who inherited the F531C variant from his father, was also found to be homozygous for a second variant in the DSP gene (Ohno et al., 2013). Upon evaluation, both of his parents were diagnosed with possible ARVC and were found to be heterozygous for this DSP variant (Ohno et al., 2013). Furthermore, F531C has been identified in the homozygous state in two other individuals referred for cardiac genetic testing at GeneDx. This variant has also been observed in approximately 0.1% of alleles from individuals of East Asian background in the Exome Aggregation Consortium, indicating it may be a rare benign variant in this population (Lek et al., 2016; Exome Variant Server). Nevertheless, F531C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution also occurs at a position that is conserved across species. Moreover, in silico analysis predicts F531C is probably damaging to the protein structure/function. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.11

MutationAssessor

Pathogenic

3.8

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.014

Polyphen

1.0

Vest4

0.73

MutPred

0.92

Loss of stability (P = 0.125);

MVP

0.91

MPC

0.50

ClinPred

0.71

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.90

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over