The COL4A4 gene is located on chromosome 2 at q36.3 and encodes the protein collagen alpha-4(IV) chain. COL4A4 was first reported in relation to autosomal recessive Alport Syndrome (OMIM: 203780) in 2 families of a cohort of 7 families with presumed autosomal recessive Alport syndrome (Mochizuki et al 1994, PMID: 7987396). Alport syndrome is characterized by hearing loss, anterior lenticonus, and glomerular basement membrane defects that may progress to end-stage kidney disease. Patients often present with hematuria and worsening proteinuria. Kidney biopsy may identify focal segmental glomerulosclerosis and thin glomerular basement membranes with abnormal ultrastructure. Autosomal dominant inheritance has also been reported, leading to an isolated renal phenotype of hematuria, with or without structural changes and progressive disease course. Case reports of digenic inheritance with COL4A3 or COL4A5 variants also exist. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism between the reported disease entities and noted that affected families show phenotypic variability with variable expressivity. Therefore, the following disease entities have been lumped into a single disease entity: Alport syndrome 2, autosomal recessive (OMIM:203780) and Hematuria, benign familial (OMIM:141200). The preferred disease name suggested for this grouping of disorders is ‘Alport Spectrum - COL4A4’. Twenty seven pathogenic or likely pathogenic variants that have been reported in 22 probands in 5 publications (PMID: 7987396, PMID:9195222, PMID: 9792860, PMID:11961012, PMID:33532864) are included in this curation. No functional data of these variants were provided in these studies. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease association is also supported by expression (PMID: 10534397, PMID: 24522496, PMID: 31892712), protein interaction (PMID: 24522496) and biochemical studies (PMID: 10534397), and animal models (PMID: 10534397, PMID: 21196518, PMID: 24522496, PMID: 31892712). In summary, COL4A4 is definitively associated with Alport Spectrum. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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