Submissions for variant NM_000091.5(COL4A3):c.343G>A (p.Gly115Arg)

gnomAD frequency: 0.00001  dbSNP: rs202147112

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Medical Genetics, University of Parma	RCV001089904	SCV001245137	likely pathogenic	Autosomal recessive Alport syndrome	2020-03-11	criteria provided, single submitter	clinical testing
GeneDx	RCV001813801	SCV002061061	uncertain significance	not provided	2024-09-10	criteria provided, single submitter	clinical testing	Reported in a patient with microhematuria and suspected familial Alport syndrome in published literature; variant was reported to be paternally inherited but additional clinical information on the family was not provided (PMID: 29801666); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A3 gene; This variant is associated with the following publications: (PMID: 33369211, 29801666)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001813801	SCV002109084	likely pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 115 of the COL4A3 protein (p.Gly115Arg). This variant is present in population databases (rs202147112, gnomAD 0.02%). This missense change has been observed in individuals with autosomal dominant and recessive Alport syndrome (PMID: 29801666, 33369211). ClinVar contains an entry for this variant (Variation ID: 599069). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A3 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV001813801	SCV003834384	likely pathogenic	not provided	2022-02-15	criteria provided, single submitter	clinical testing
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV000735661	SCV005073735	pathogenic	Autosomal dominant Alport syndrome	2024-05-01	criteria provided, single submitter	research	Likely pathogenic by Deafness Variation Database and by 3 submissions to ClinVar, and pathogenic by one ClinVar submission.
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV004760761	SCV005367983	pathogenic	Alport syndrome 3b, autosomal recessive	2024-09-18	criteria provided, single submitter	research	The c.343G>A:p.(Gly115Arg) variant was detected in a patient with a sloping audiogram, normal-to-moderate hearing loss, in compound heterozygosity with another variant, c.1022G>A:p.(Arg341His). The c.343G>A:p.(Gly115Arg) variant was previously classified as LP and P by deafness variation database and by several ClinVar submissions.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001089904	SCV005381168	likely pathogenic	Autosomal recessive Alport syndrome	2024-08-13	criteria provided, single submitter	clinical testing	Variant summary: COL4A3 c.343G>A (p.Gly115Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249438 control chromosomes. c.343G>A has been reported in the literature in individuals affected with autosomal dominand and autosomal recessive Alport Syndrome (Bullich_2018, Uliana_2021, Furlano_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29801666, 33838161, 33369211). ClinVar contains an entry for this variant (Variation ID: 599069). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000735661	SCV000863802	likely pathogenic	Autosomal dominant Alport syndrome	2018-01-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003411689	SCV004107416	pathogenic	COL4A3-related disorder	2023-12-08	no assertion criteria provided	clinical testing	The COL4A3 c.343G>A variant is predicted to result in the amino acid substitution p.Gly115Arg. This variant affects a glycine (Gly) residue of the conserved triple helical domain (residues 43-1438) of the COL4A3 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/). This variant has been reported in the heterozygous state in an individual with autosomal dominant Alport syndrome (Supplementary Table 3 in Bullich et al. 2018. PubMed ID: 29801666), and it has been reported along with a second pathogenic COL4A3 variant a family with autosomal recessive Alport syndrome (Supplementary Table 1 in Uliana et al. 2020. PubMed ID: 33369211). In addition, at PreventionGenetics, we have found this variant in presumably unrelated patients tested for glomerular kidney disease or hearing loss. This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.