Submissions for variant NM_000091.5(COL4A3):c.2585G>C (p.Gly862Ala)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV003408498	SCV004110224	likely pathogenic	COL4A3-related disorder	2023-04-17	criteria provided, single submitter	clinical testing	The COL4A3 c.2585G>C variant is predicted to result in the amino acid substitution p.Gly862Ala. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. The p.Gly862 residue is located in the conserved triple helical domain, where substitutions of the glycine are usually pathogenic (UniProt residues 43-1438, Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK21582/). This variant is interpreted as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003689084	SCV004433255	uncertain significance	not provided	2023-08-08	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 862 of the COL4A3 protein (p.Gly862Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL4A3-related conditions. 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. 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.
Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	RCV004699173	SCV005201107	pathogenic	Autosomal dominant Alport syndrome	2024-09-05	criteria provided, single submitter	clinical testing	Alternative variant chr2:227282460 G⇒C (Gly862Arg) is classified Likely Pathogenic, 1 star, by ClinVar (confirmed using the germline classifier).Alternative variant chr2:227282460 G⇒A (Gly862Ser) is classified Likely Pathogenic, 0 stars, by ClinVar (confirmed using the germline classifier).2 pathogenic alternative variants identified (PM5). MetaRNN = 0.994 is greater than 0.939 ⇒ strong pathogenic (PP3). Hot-spot of length 17 amino-acids has 13 missense/in-frame variants (5 pathogenic variants, 8 uncertain variants and no benign), which qualifies as moderate pathogenic.UniProt protein CO4A3_HUMAN region of interest 'Disordered' has 471 missense/in-frame variants (184 pathogenic variants, 263 uncertain variants and 24 benign variants), which qualifies as moderate pathogenic.UniProt protein CO4A3_HUMAN region of interest 'Triple-helical region' has 720 missense/in-frame variants (270 pathogenic variants, 408 uncertain variants and 42 benign variants), which qualifies as moderate pathogenic (PM1). Variant not found in gnomAD genomes, good gnomAD genomes coverage = 30.0.GnomAD exomes homozygous allele count = 0 is less than 2 for AD/AR gene COL4A3, good gnomAD exomes coverage = 31.0 (PM2).We observed this variant in a 8-year-old girl patient with Alport Syndrome.