This variant is denoted Trp306Stop (aka W306X) at the protein level and c.918 G>A at the cDNA level. A G>A nucleotide substitution was identified in exon 8 of the DSG2 gene, resulting in the replacement of the normal Tryptophan codon (TGG) with a Stop codon (TGA) at amino acid position 306 in the desmoglein-2 gene, was identified. Autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle; with time, it may also involve the left ventricle. The presentation of disease is highly variable even within families, and affected individuals may not always meet established clinical criteria. ARVC may be caused by mutations in at least seven genes, which together account for ARVC in 40-50% of patients (6). At least 12% of patients with autosomal dominant ARVC have been reported to have a mutation in the DSG2 gene ( McNally E et al., Gene Review; OMM). The Trp306Stop mutation and the Arg49His mutation (also reported as Arg48His/Trp305Stop due to a difference in nomenclature) have been seen together in at least one patient (Awad, M et al., 2006) and are reported together in other publications, but it is unclear if data stem from unrelated probands with ARVC (Den Haan, A et al., 2009; Tan B et al., 2010). In the Awad 2006 (Awad, M et al., 2006) report, the proband's unaffected mother and sister also harbored the Trp306Stop mutation, but not the Arg49His mutation (Awad, M et al., 2006). Trp306Stop is predicted to cause loss of normal protein function either through abnormal, prematurely truncated protein, or by absence of protein product due to nonsense-mediated mRNA decay. The Arg49His mutation has been reported in up to four other patients with ARVC, and has not been detected in at least 400 population-matched control chromosomes (Den Haan, A et al., 2009; Xu T et al., 2010; Barahona-Dussault, C et al., 2010). The Arg49 residue is reported to be absolutely conserved in all species and sub-types of desmoglein, and replacement with other residues is predicted to abolish a cleavage site in demoglein, disrupting production of mature, functional protein (Awad, M et al., 2006). Also, Arg49His has been seen in other unrelated individuals at GeneDx. The variant is found in ARVC panel(s).
ClinVar Genomic variation as it relates to human health
Help
- Interpretation:
-
Pathogenic
- Review status:
- criteria provided, single submitter
- Submissions:
- 2 (Most recent: Jul 13, 2017)
- Last evaluated:
- Oct 5, 2011
- Accession:
- VCV000016811.2
- Variation ID:
- 16811
- Description:
- single nucleotide variant
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NM_001943.5(DSG2):c.918G>A (p.Trp306Ter)
- Allele ID
- 31850
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 18q12.1
- Genomic location
- 18: 31524792 (GRCh38) GRCh38 UCSC
- 18: 29104755 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceLRG_397t1:c.918G>A LRG_397p1:p.Trp306Ter LRG_397:g.31551G>A NC_000018.10:g.31524792G>A NC_000018.9:g.29104755G>A NG_007072.3:g.31551G>A NM_001943.5:c.918G>A MANE Select NP_001934.2:p.Trp306Ter nonsense - Protein change
- W306*
- Other names
- W305*
- p.W306*:TGG>TGA
- Canonical SPDI
- NC_000018.10:31524791:G:A
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- -
- Links
- dbSNP: rs121913007
- ClinGen: CA022354
- OMIM: 125671.0002
- VarSome
- Comment on variant
- NCBI staff reviewed the sequence information reported in PubMed 16773573 to determine the location of this allele on current reference sequence.
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Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Pathogenic | 1 | criteria provided, single submitter | Oct 5, 2011 | RCV000181248.2 | |
| Pathogenic | 1 | no assertion criteria provided | Jul 1, 2006 | RCV000018304.31 |
Help
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation | Variation viewer | Related variants | ||
|---|---|---|---|---|---|---|
| HI score Help | TS score Help | Within gene | All | |||
| DSG2 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
655 | 1113 | |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | Supporting information
(See all) |
|---|---|---|---|---|
|
Pathogenic
(Oct 05, 2011)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Allele origin:
germline
|
GeneDx
Accession: SCV000233527.9
Submitted: (Jul 13, 2017) |
Comment:
This variant is denoted Trp306Stop (aka W306X) at the protein level and c.918 G>A at the cDNA level. A G>A nucleotide substitution was identified in … (more)
This variant is denoted Trp306Stop (aka W306X) at the protein level and c.918 G>A at the cDNA level. A G>A nucleotide substitution was identified in exon 8 of the DSG2 gene, resulting in the replacement of the normal Tryptophan codon (TGG) with a Stop codon (TGA) at amino acid position 306 in the desmoglein-2 gene, was identified. Autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle; with time, it may also involve the left ventricle. The presentation of disease is highly variable even within families, and affected individuals may not always meet established clinical criteria. ARVC may be caused by mutations in at least seven genes, which together account for ARVC in 40-50% of patients (6). At least 12% of patients with autosomal dominant ARVC have been reported to have a mutation in the DSG2 gene ( McNally E et al., Gene Review; OMM). The Trp306Stop mutation and the Arg49His mutation (also reported as Arg48His/Trp305Stop due to a difference in nomenclature) have been seen together in at least one patient (Awad, M et al., 2006) and are reported together in other publications, but it is unclear if data stem from unrelated probands with ARVC (Den Haan, A et al., 2009; Tan B et al., 2010). In the Awad 2006 (Awad, M et al., 2006) report, the proband's unaffected mother and sister also harbored the Trp306Stop mutation, but not the Arg49His mutation (Awad, M et al., 2006). Trp306Stop is predicted to cause loss of normal protein function either through abnormal, prematurely truncated protein, or by absence of protein product due to nonsense-mediated mRNA decay. The Arg49His mutation has been reported in up to four other patients with ARVC, and has not been detected in at least 400 population-matched control chromosomes (Den Haan, A et al., 2009; Xu T et al., 2010; Barahona-Dussault, C et al., 2010). The Arg49 residue is reported to be absolutely conserved in all species and sub-types of desmoglein, and replacement with other residues is predicted to abolish a cleavage site in demoglein, disrupting production of mature, functional protein (Awad, M et al., 2006). Also, Arg49His has been seen in other unrelated individuals at GeneDx. The variant is found in ARVC panel(s). (less)
|
|
Pathogenic
(Jul 01, 2006)
|
no assertion criteria provided
Method: literature only
|
ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 10
Allele origin:
germline
|
OMIM
Accession: SCV000038583.5
Submitted: (Dec 30, 2010) |
|
Functional evidence
Help| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy. | Awad MM | American journal of human genetics | 2006 | PMID: 16773573 |
Text-mined citations for rs121913007...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Dec 04, 2021