ClinVar

Description

The de novo missense variant c.179G>C has not previously been reported in the literature or public variant repositories (ClinVar and LOVD) and is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.179G>C variant in the GJA1 is located in exon 2 of this 2-exon gene and is predicted to replace an evolutionarily conserved glycine amino acid with alanine at position 60 in the extracellular loop of the encoded protein. In silico predictions are in favor of a damaging effect for p.(Gly60Ala) [(CADD v1.6 = 25.4, REVEL = 0.966)]; however, there are no functional studies to support or refute these predictions. A different amino acid substitution at the same residue p.Gly60Ser has been reported in a mice model with the ODDD phenotype [PMID: 16155213]. In vivo and in vitro studies revealed that the mutant Cx43 protein p.Gly60Ser acts in a dominant-negative fashion to disrupt gap junction assembly and function [PMID:16155213]. In addition to the classic features of ODDD, these mutant mice also showed a decreased bone mass and mechanical strength and altered hematopoietic stem cell and progenitor populations [PMID: 16155213]. Based on available evidence, this de novo missense variant c.179G>C, (p.(Gly60Ala)) identified in the GJA1 gene is classified as Likely pathogenic.