ClinVar Miner

Submissions for variant NM_033380.3(COL4A5):c.1276G>A (p.Gly426Arg) (rs104886111)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520914 SCV000617326 pathogenic not provided 2017-08-03 criteria provided, single submitter clinical testing The G426R variant has been published as a pathogenic variant in association with Alport syndrome (Nagel et al., 2005). The G426R variant is not observed in large population cohorts (Lek et al., 2016). The G426R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, approximately one-third of pathogenic varaints associated with Alport syndrome are reported to be missense variants in which a Glycine residue is replaced by any other amino acid in this central region of the protein that contains numerous Gly-X-Y repeats. We interpret G426R as a pathogenic variant.
Gharavi Laboratory,Columbia University RCV000520914 SCV000809392 likely pathogenic not provided 2018-09-16 criteria provided, single submitter research
Invitae RCV000520914 SCV001591119 pathogenic not provided 2020-10-07 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 426 of the COL4A5 protein (p.Gly426Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Alport syndrome (PMID: 21505094, 15954103, 30647093, Invitae). ClinVar contains an entry for this variant (Variation ID: 24393). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Research and Development, ARUP Laboratories RCV000021272 SCV000041938 pathogenic Alport syndrome 1, X-linked recessive 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000021272 SCV001192774 pathogenic Alport syndrome 1, X-linked recessive 2019-09-25 no assertion criteria provided clinical testing

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