Submissions for variant NM_000091.5(COL4A3):c.1985G>A (p.Gly662Glu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003441569	SCV004168946	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A3 gene, where the majority of pathogenic missense variants occur; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28780565)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003441569	SCV004294018	uncertain significance	not provided	2023-03-20	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Gly662 amino acid residue in COL4A3. Other variant(s) that disrupt this residue have been observed in individuals with COL4A3-related conditions (PMID: 26809805), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt COL4A3 protein function. This missense change has been observed in individual(s) with clinical features of Alport syndrome (PMID: 28780565). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 662 of the COL4A3 protein (p.Gly662Glu).