Submissions for variant NM_000092.5(COL4A4):c.446G>T (p.Gly149Val)

dbSNP: rs374815903

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001251466	SCV001427166	pathogenic	Benign familial hematuria	2018-12-28	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_000092.4(COL4A4):c.446G>T, has been identified in exon 7 of 48 of the COL4A4 gene. The variant is predicted to result in a major amino acid change from glycine to valine at position 149 of the protein (NP_000083.3(COL4A4):p.(Gly149Val)). The glycine residue at this position has very high conservation (100 vertebrates, UCSC), and affects a glycine residue of the triple helical region containing GLY-X-Y repeats. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.0004% (1 heterozygote), and an alternative residue change has also been reported in the gnomAD database at a frequency of 0.0004% (1 heterozygote). The variant has previously been reported as likely pathogenic (ClinVar). A different variant in the same codon resulting in a change to glutamic acid has also been reported in patients with Alport syndrome (Weber S. et al. (2016)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Invitae	RCV001320831	SCV001511634	pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 149 of the COL4A4 protein (p.Gly149Val). This variant is present in population databases (rs374815903, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of Alport syndrome (PMID: 32939031; Invitae). ClinVar contains an entry for this variant (Variation ID: 369941). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000408863	SCV000484908	likely pathogenic	Autosomal recessive Alport syndrome		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001833487	SCV002084174	uncertain significance	Alport syndrome	2020-05-31	no assertion criteria provided	clinical testing