Submissions for variant NM_033380.3(COL4A5):c.2288G>A (p.Gly763Glu)

dbSNP: rs281874689

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000021382	SCV000537722	pathogenic	X-linked Alport syndrome	2014-08-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001067665	SCV001232735	pathogenic	not provided	2024-09-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 763 of the COL4A5 protein (p.Gly763Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Alport syndrome (PMID: 20378821, 27353043; internal data). ClinVar contains an entry for this variant (Variation ID: 24503). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL4A5 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL4A5. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic.
Precision Medicine Center, Zhengzhou University	RCV000021382	SCV001593037	likely pathogenic	X-linked Alport syndrome		criteria provided, single submitter	research	PM1:Located in a mutational hot spot PM2:not found in gnomAD PP2:Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP3:Multiple lines of computational evidence support a deleterious effect on the gene or gene product PP4:Patient's phenotype is highly specific for a disease
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000021382	SCV003800790	pathogenic	X-linked Alport syndrome	2023-01-11	criteria provided, single submitter	clinical testing	Variant summary: COL4A5 c.2288G>A (p.Gly763Glu) results in a non-conservative amino acid change to a conserved residue in the encoded protein sequence. Two other missense variants affecting this residue have been found in association with Alport syndrome (HGMD). Alterations of glycine residues within the collagen triple-helix are common mechanisms of disease. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183186 control chromosomes. c.2288G>A has been reported in the literature in multiple individuals affected with Alport Syndrome 1, X-Linked Recessive (Pont-Kingdon_2009, Bekheirnia_2010, Wang_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.