rs794728093

chr18-31524701-AGCTTGAAGGGAT-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PP3 PP5

The NM_001943.5(DSG2):c.829_840del(p.Leu277_Met280del) variant causes a splice acceptor, coding sequence change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: DSG2 NM_001943.5 splice_acceptor, coding_sequence
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5
• Conservation: PhyloP100: 9.02

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.05510873 fraction of the gene. Cryptic splice site detected, with MaxEntScore 10, offset of 0 (no position change), new splice context is: catgtgttcatgttttgcAGgtt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 18-31524701-AGCTTGAAGGGAT-A is Pathogenic according to our data. Variant chr18-31524701-AGCTTGAAGGGAT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199824.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Pathogenic=1, Likely_pathogenic=1}. Variant chr18-31524701-AGCTTGAAGGGAT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSG2	NM_001943.5	c.829_840del	p.Leu277_Met280del	splice_acceptor_variant, coding_sequence_variant	8/15	ENST00000261590.13
DSG2	XM_047437315.1	c.295_306del	p.Leu99_Met102del	splice_acceptor_variant, coding_sequence_variant	9/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSG2	ENST00000261590.13	c.829_840del	p.Leu277_Met280del	splice_acceptor_variant, coding_sequence_variant	8/15	1	NM_001943.5	P1
DSG2	ENST00000682087.2	n.660_671del		splice_acceptor_variant, non_coding_transcript_exon_variant	6/6
DSG2	ENST00000683614.2	n.660_671del		splice_acceptor_variant, non_coding_transcript_exon_variant	6/7

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461834 Hom.: 0 AF XY: 0.0000275 AC XY: 20 AN XY: 727214

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: 0.0000405

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74376

Gnomad4 AFR AF: 0.00

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiomyopathy Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 18, 2023	This variant deletes 12 nucleotides from exon 8 of the DSG2 gene, resulting in an in-frame deletion of 4 amino acids. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 3 unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy and it has been observed to segregate with disease in one of the families (PMID: 17105751, 19279339, 23671136). One of these individuals also carried a pathogenic truncation variant in the PKP2 gene that could explain the observed phenotype (PMID: 23671136). This variant has been identified in 1/280596 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 03, 2021	- -

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2015	The c.829_840del12 mutation has been reported as a disease-causing mutation in association with ARVC (Syrris P et al., 2007, Asimaki A et al., 2009). This mutation was present in a parent and child, both of whom met Task Force criteria for the diagnosis of ARVC. Another child from this family with autopsy-confirmed ARVC also harbored this mutation (Syrris P et al., 2007). The mutation was absent from 200 ethnicity-matched control samples in this study. Furthermore, immunohistochemical analysis of cardiac tissue from autopsy in an individual with this mutation showed marked reduction in immunoreactivity for plakophilin2 and desmoplakin when compared to control tissue (Asimaki A et al., 2009). This mutation results in the deletion of 4 amino acids at the beginning of exon 8, that it is predicted to destroy the normal acceptor site of intron 7 and to create a cryptic splice acceptor site in exon 8. In addition, the NHLBI ESP Exome Variant Server reports c.829_840del12 was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, c.829_840del12 in the DSG2 gene is interpreted as a disease-causing mutation. -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Nov 12, 2021	- -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 26, 2023

This variant deletes 12 nucleotides from exon 8 of the DSG2 gene, resulting in an in-frame deletion of 4 amino acids. Splicing prediction tools suggest that this variant may not disrupt RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported to segregate with arrhythmogenic right ventricular cardiomyopathy in a small family (PMID: 17105751), as well as in two unrelated individuals with this condition (PMID: 19279339, 23671136). One of these individuals also carried a pathogenic truncation variant in the PKP2 gene that could explain the observed phenotype (PMID: 23671136). This variant has been identified in 1/280596 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Arrhythmogenic right ventricular dysplasia 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This variant, c.829_840del, results in the deletion of 4 amino acid(s) of the DSG2 protein (p.Leu277_Met280del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs779260860, gnomAD 0.0008%). This variant has been observed in individual(s) with DSG2-related conditions (PMID: 17105751). This variant is also known as c.829-1delGCTTGAAGGGAT (G277fsX278), 829_840delCTTGAAGGCATG. ClinVar contains an entry for this variant (Variation ID: 199824). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2019

The c.829_840del12 variant (also known as p.L277_M280del) is located in coding exon 8 of the DSG2 gene. This variant results from an in-frame CTTGAAGGGATG deletion at nucleotide positions 829 to 840. This results in the deletion of four amino acids between codons 277 and 280. This variant was detected in two related individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC), who shared an additional first degree relative with sudden cardiac death due to ARVC, but who did not have genetic testing (Syrris P et al. Eur. Heart J., 2007 Mar;28:581-8). These amino acid positions are generally not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs794728093; hg19: chr18-29104664;