Submissions for variant NM_000092.5(COL4A4):c.2182G>A (p.Gly728Arg)

gnomAD frequency: 0.00001  dbSNP: rs202243658

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002037149	SCV002111307	uncertain significance	not provided	2023-08-11	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. 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 COL4A4 protein function. ClinVar contains an entry for this variant (Variation ID: 1345257). This variant has not been reported in the literature in individuals affected with COL4A4-related conditions. This variant is present in population databases (rs202243658, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 728 of the COL4A4 protein (p.Gly728Arg).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004785337	SCV005399686	likely pathogenic	Alport syndrome	2024-10-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Loss of function is a known mechanism of disease for this gene and is associated with Alport syndrome. Dominant negative is a suspected mechanism of disease for this gene as it is a structural protein (PMIDs: 12028435, 24046192). (I) 0108 - This gene is associated with both recessive and dominant disease. Alport syndrome typically has biallelic inheritance, although rare cases of monoallelic inheritance have been reported (PMID: 28704582). Thin basement membrane nephropathy (TBMN) and focal segmental glomerulosclerosis (FSGS) are associated with autosomal dominant inheritance (OMIM, PMIDs: 16467446, 17942953). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 (11 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional Gly-X-Y motif (DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Gly728Glu) has been observed in a compound heterozygous individual with autosomal recessive Alport syndrome (PMID: 22887978). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported once as a VUS in ClinVar by a clinical laboratory. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV004728847	SCV005335839	likely pathogenic	COL4A4-related disorder	2024-05-10	no assertion criteria provided	clinical testing	The COL4A4 c.2182G>A variant is predicted to result in the amino acid substitution p.Gly728Arg. This variant affects a glycine (Gly) residue of the conserved triple helical domain (residues 65-1459) of the COL4A4 protein (uniprot.org), where substitutions of the glycine (Gly) residue are usually pathogenic (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). In a genetic study of diabetic kidney disease (DKD) patients, this variant has been reported in an individual who was also found to have multiple variants in other kidney disease-related genes; and the clinical consequence of the p.Gly728Arg variant in COL4A4 in this individual was unspecified (Patient FS180133 in Supplemental Table 4 of Lazaro-Guevara et al. 2021. PubMed ID: 33774617). Of note, a different substitution at the same codon, defined as c.2183G>A (p.Gly728Glu), was reported with a pathogenic splice variant in an individual with autosomal recessive COL4A4 nephropathy (Zhang et al. 2012. PubMed ID: 22887978). In addition, in the same exon (exon 28), substitutions of the flanking glycine (Gly) residues have been reported to be pathogenic for autosomal dominant or recessive COL4A4 nephropathy (see for example, p.Gly748Ser in Papazachariou et al. 2017. PubMed ID: 28632965 and Popp et al. 2022. PubMed ID: 36100708; p.Gly757Glu in Boeckhaus et al. 2021. PubMed ID: 33040356). Moreover, at other glycine (Gly) residues within this domain, substitutions of a glycine (Gly) with an arginine (Arg) have been widely reported to be pathogenic for autosomal dominant or recessive COL4A4 nephropathy (see for example, autosomal dominant cases: p.Gly466Arg in Weber et al. 2016. PubMed ID: 26809805 and p.Gly651Arg in Gao et al. 2022. PubMed ID: 36685964; autosomal recessive cases: p.Gly170Arg in Supplementary Table 1 of Morinière et al. 2014. PubMed ID: 24854265 and p.Gly864Arg in Storey et al. 2013. PubMed ID: 24052634). This variant is reported in 0.0018% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic for both autosomal dominant and autosomal recessive COL4A4-related conditions.