NM_001943.3(DSG2):c.146G>A (p.Arg49His) AND Arrhythmogenic right ventricular cardiomyopathy, type 10

Clinical significance:conflicting data from submitters, Likely pathogenic(1);Pathogenic(1) (Last evaluated: Aug 2, 2013)

Review status:(0/4)0 stars out of maximum of 4 stars

conflicting data from submitters (classified by multiple submitters)

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000018303.23

Allele description [Variation Report for NM_001943.3(DSG2):c.146G>A (p.Arg49His)]

Note:
NCBI staff reviewed the sequence information reported in PubMed 16773573 to determine the location of this allele on current reference sequence.
Gene:
DSG2:desmoglein 2 [Gene - OMIM]
Variant type:
single nucleotide variant
Cytogenetic location:
18q12.1
Genomic location:
Preferred name:
NM_001943.3(DSG2):c.146G>A (p.Arg49His)
HGVS:
  • NC_000018.10:g.31519867G>A
  • NG_007072.3:g.26626G>A
  • NM_001943.3:c.146G>A
  • NP_001934.2:p.Arg49His
  • NC_000018.9:g.29099830G>A
  • NG_007072.2:g.26626G>A
  • c.146G>A
Protein change:
R49H
Links:
OMIM: 125671.0001; dbSNP: 121913006
NCBI 1000 Genomes Browser:
rs121913006
Molecular consequence:
  • NM_001943.3:c.146G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Arrhythmogenic right ventricular cardiomyopathy, type 10 (ARVD10)
Synonyms:
ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 10; Arrhythmogenic right ventricular dysplasia 10; Arrhythmogenic right ventricular cardiomyopathy 10
Identifiers:
MedGen: C1857777; OMIM: 610193

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Assertion and evidence details

Submission AccessionSubmitterReview StatusClinical Significance
(Last evaluated)
OriginMethodConsequenceCitations
SCV000038582OMIMPathogenic
(Aug 2, 2013)
germlineliterature only

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

SCV000060922Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicineclassified by single submitterLikely pathogenic
(Dec 19, 2012)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedAlleles observedFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providedliterature only, clinical testing

Citations

PubMed

DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Awad MM, Dalal D, Cho E, Amat-Alarcon N, James C, Tichnell C, Tucker A, Russell SD, Bluemke DA, Dietz HC, Calkins H, Judge DP.

Am J Hum Genet. 2006 Jul;79(1):136-42. Epub 2006 Apr 28.

PubMed [citation]
PMID:
16773573
PMCID:
PMC1474134

Sporadic arrhythmogenic right ventricular cardiomyopathy/dysplasia due to a de novo mutation.

Gandjbakhch E, Fressart V, Bertaux G, Faivre L, Simon F, Frank R, Fontaine G, Villard E, Coirault C, Hainque B, Charron P.

Europace. 2009 Mar;11(3):379-81. doi: 10.1093/europace/eun378. Epub 2009 Jan 16.

PubMed [citation]
PMID:
19151369
See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000038582.1

#EthnicityAlleles ObservedChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In a patient with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD10; 610193), Awad et al. (2006) found compound heterozygosity for mutations in the DSG2 gene. One was a G-to-A transition at nucleotide 134 in exon 3, which results in the substitution of a conserved arginine with histidine (R48H). These arginines occur as the first and fourth amino acids within the RXKR furin-cleavage motif. The other mutation was a nonsense mutation (125671.0002). The patient had structural and functional right ventricular abnormality, ECG depolarization abnormality, ECG repolarization abnormality, and diagnostic arrhythmias.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodVariant allelesAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine, SCV000060922.2

#EthnicityAlleles ObservedChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (6)

Description

The Arg49His variant in DSG2 has been reported in at least 8 individuals with clinical features or a diagnosis of ARVC, including one de novo occurrence, and was absent from 820 control chromosomes (Awad 2006, den Haan 2009, Gandjbakch 2009, Xu 2010, Barahona-Dussault 2010, Fressart 2010). The Arg49His variant has not been identified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs121913006) and this low frequency supports a pathogenic role. A presence in other populations cannot be excluded. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, the available evidence for this variant suggests that it is disease-causing, but additional information is still needed to establish this with confidence.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodVariant allelesAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

Last Updated: Feb 27, 2015

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