NM_001943.5(DSG2):c.3G>A (p.Met1Ile) AND Arrhythmogenic right ventricular dysplasia 10

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 17, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000814563.7

Allele description [Variation Report for NM_001943.5(DSG2):c.3G>A (p.Met1Ile)]

NM_001943.5(DSG2):c.3G>A (p.Met1Ile)

Genes:

LOC130062340:ATAC-STARR-seq lymphoblastoid silent region 9384 [Gene]
DSG2:desmoglein 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q12.1

Genomic location:

Preferred name:

NM_001943.5(DSG2):c.3G>A (p.Met1Ile)

HGVS:

NC_000018.10:g.31498254G>A
NG_007072.3:g.5013G>A
NM_001943.5:c.3G>AMANE SELECT
NP_001934.2:p.Met1Ile
LRG_397t1:c.3G>A
LRG_397:g.5013G>A
NC_000018.9:g.29078217G>A
NM_001943.3:c.3G>A

Protein change:

M1I

Links:

dbSNP: rs1021457619

NCBI 1000 Genomes Browser:

rs1021457619

Molecular consequence:

NM_001943.5:c.3G>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001943.5:c.3G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Arrhythmogenic right ventricular dysplasia 10
Synonyms:: ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 10; Arrhythmogenic right ventricular cardiomyopathy, type 10; Arrhythmogenic right ventricular dysplasia/cardiomyopathy, type 10; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012434; MedGen: C1857777; OMIM: 610193

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000954976	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17105751, 20829228, 19151369, 28492532
SCV001369398	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 12, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000954976

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 17, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001369398

Centre for Mendelian Genomics, University Medical Centre Ljubljana

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 12, 2019)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Desmoglein-2 mutations in arrhythmogenic right ventricular cardiomyopathy: a genotype-phenotype characterization of familial disease.

Syrris P, Ward D, Asimaki A, Evans A, Sen-Chowdhry S, Hughes SE, McKenna WJ.

Eur Heart J. 2007 Mar;28(5):581-8. Epub 2006 Nov 14.

PubMed [citation]

PMID:: 17105751

De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy.

Klauke B, Kossmann S, Gaertner A, Brand K, Stork I, Brodehl A, Dieding M, Walhorn V, Anselmetti D, Gerdes D, Bohms B, Schulz U, Zu Knyphausen E, Vorgerd M, Gummert J, Milting H.

Hum Mol Genet. 2010 Dec 1;19(23):4595-607. doi: 10.1093/hmg/ddq387. Epub 2010 Sep 9.

PubMed [citation]

PMID:: 20829228

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000954976.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change affects the initiator methionine of the DSG2 mRNA. The next in-frame methionine is located at codon 179. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 17105751, 20829228). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 657863). This variant disrupts the p.Arg49 amino acid residue in DSG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19151369). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001369398.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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