Submissions for variant NM_000092.5(COL4A4):c.1334G>C (p.Gly445Ala)

gnomAD frequency: 0.00005  dbSNP: rs548019779

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001245318	SCV001418599	uncertain significance	not provided	2022-09-01	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 445 of the COL4A4 protein (p.Gly445Ala). This variant is present in population databases (rs548019779, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with COL4A4-related conditions. ClinVar contains an entry for this variant (Variation ID: 830015). 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. 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.
GeneDx	RCV001245318	SCV001796942	uncertain significance	not provided	2023-07-03	criteria provided, single submitter	clinical testing	Observed with the p.(P857L) variant in the COL4A4 gene in a patient with renal features of Alport syndrome in published literature, but the phase of these variants is unknown (Ben Moshe et al., 2022); Observed with the p.(P857L) variant on the same allele (in cis) in unrelated individuals referred for genetic testing at GeneDx; 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 COL4A4 gene; This variant is associated with the following publications: (PMID: 36239278)
PreventionGenetics, part of Exact Sciences	RCV003396621	SCV004119124	uncertain significance	COL4A4-related condition	2023-08-06	criteria provided, single submitter	clinical testing	The COL4A4 c.1334G>C variant is predicted to result in the amino acid substitution p.Gly445Ala. This variant along with the c.2570C>T (p.Pro857Leu) variant was reported in a patient with nephrotic syndrome; however, pathogenicity was not established and phase of these variants was not determined (Ben Moshe et al. 2022. PubMed ID: 36239278). PreventionGenetics internal data suggests these two variants are likely to commonly occur on the same allele. This variant results in a Gly substitution in the conserved triple helical domain (residues 65 – 1459) of the COL4A4 protein (uniprot.org). However, this is a Gly to Ala substitution and the majority of pathogenic variants in COL4A4 substitute a glycine residue to a bulkier amino acid in the triple-helical domain (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant is reported in 0.055% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-227958876-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV001029983	SCV001192785	likely pathogenic	Autosomal dominant Alport syndrome	2019-10-07	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001832366	SCV002084158	uncertain significance	Alport syndrome	2019-12-31	no assertion criteria provided	clinical testing