ClinVar Miner

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

gnomAD frequency: 0.00020  dbSNP: rs121434557
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487058 SCV000565040 uncertain significance not provided 2021-10-06 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate a damaging effect as this variant results in reduced cell-cell coupling and connexin 40 activity and mice that are heterozygous for the A96S variant exhibit significantly reduced atrial conduction velocities and strongly prolonged episodes of atrial fibrillation (Gollob et al., 2006; Lbkemeier et al., 2013); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 16998; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23292621, 28074886, 24144883, 21597036, 26503720, 16790700, 24656738, 23040431, 28457700, 24626989, 9588401, 24060583, 26582918, 33664309, 30847666, 31589614)
Invitae RCV001063672 SCV001228529 uncertain significance Atrial standstill 1; Atrial fibrillation, familial, 11 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 96 of the GJA5 protein (p.Ala96Ser). This variant is present in population databases (rs121434557, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of GJA5-related conditions (PMID: 16790700, 24144883, 28074886, 30847666). ClinVar contains an entry for this variant (Variation ID: 16998). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GJA5 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GJA5 function (PMID: 16790700, 24060583, 26503720, 28457700). 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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