ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.889G>A (p.Asp297Asn) (rs751012696)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181212 SCV000233490 uncertain significance not provided 2017-04-18 criteria provided, single submitter clinical testing The D297N variant in the DSG2 gene has been reported in association with ARVC (Bhuiyan et al., 2009; Tan et al., 2010). Bhuiyan et al. reported D297N as homozygous in a 36 year old male patient with ARVC. Also, one other patient diagnosed with ARVC was reported as heterozygous for the D297N variant but did not present with symptoms until after 50 years of age (Tan et al., 2010). Another variant at this same residue (D297G) and variants in nearby residues (K294E) have been reported in HGMD in association with ARVC (Stenson et al., 2014). Furthermore, D297N was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, Cox et al. reported the D297N substitution as an unclassified variant based on in silico predictors being inconsistent (Cox et al., 2011).In summary, while there have been at least two published reports indicating an association between the D297N variant and ARVC, additional evidence is needed to determine whether this variant is pathogenic or benign.
Invitae RCV000558472 SCV000641997 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2018-07-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 297 of the DSG2 protein (p.Asp297Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs751012696, ExAC 0.009%). This variant has been reported in two individuals affected with arrhythmogenic right ventriculardysplasia (ARVD) (PMID: 20031616, 20857253). However, in one of these cases it was found in homozygosis and in the other one co-occurring with a pathogenic variant in the PKP2 gene. ClinVar contains an entry for this variant (Variation ID: 199804). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare missense change that has been found in two ARVD patients.  In the absence of confirmed segregation or functional studies, at this time this change has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV001189659 SCV001356990 uncertain significance Cardiomyopathy 2018-12-14 criteria provided, single submitter clinical testing

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