ClinVar Miner

Submissions for variant NM_181703.4(GJA5):c.286G>T (p.Ala96Ser) (rs121434557)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487058 SCV000565040 uncertain significance not provided 2018-12-13 criteria provided, single submitter clinical testing The A96S variant of uncertain significance in the GJA5 gene has been reported in association with atrial fibrillation (Gollob et al., 2006; Christophersen et al., 2013; Olesen et al., 2014). Gollob et al. (2006) initially reported this variant in an individual with idiopathic atrial fibrillation; however, the A96S variant was also observed in one control individual. This variant was observed in the affected individual's two sons who did not have a history of atrial fibrillation; however, both had abnormally prolonged P-wave duration on ECG (Gollob et al., 2006). This variant has also been reported in one individual who died at 3 months of age and harbored additional cardiogenetic variants (Neubauer et al., 2017). The A96S variant is observed in 33/276868 (0.01%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, functional characterization of A96S showed this variant reduced cell-cell coupling and connexin 40 activity (Gollob et al., 2006). In addition, mice that are heterozygous for the A96S variant exhibit significantly reduced atrial conduction velocities and strongly prolonged episodes of atrial fibrillation (Lübkemeier et al., 2013). Finally, the A96S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487058 SCV001147412 uncertain significance not provided 2018-07-01 criteria provided, single submitter clinical testing
Invitae RCV001063672 SCV001228529 uncertain significance Atrial standstill 1; Atrial fibrillation, familial, 11 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 96 of the GJA5 protein (p.Ala96Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs121434557, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in several individuals affected with atrial fibrillation (PMID: 16790700, 28457700, 24060583). ClinVar contains an entry for this variant (Variation ID: 16998). This variant has been reported to affect GJA5 protein function (PMID: 16790700, 28457700, 24060583). 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.
OMIM RCV000018521 SCV000038803 pathogenic Atrial fibrillation, familial, 11 2006-06-22 no assertion criteria provided literature only

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