ClinVar Miner

Submissions for variant NM_000092.5(COL4A4):c.446G>T (p.Gly149Val) (rs374815903)

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Total submissions: 3
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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 uncertain significance not provided 2020-02-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 149 of the COL4A4 protein (p.Gly149Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs374815903, ExAC 0.009%). This variant has not been reported in the literature in individuals with COL4A4-related disease. ClinVar contains an entry for this variant (Variation ID: 369941). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000408863 SCV000484908 likely pathogenic Alport syndrome, autosomal recessive no assertion criteria provided clinical testing

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