ClinVar Miner

Submissions for variant NM_000091.4(COL4A3):c.686G>T (p.Arg229Leu) (rs188942711)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658171 SCV000779942 uncertain significance not provided 2018-05-09 criteria provided, single submitter clinical testing The c.686 G>T variant in the COL4A3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.686 G>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In-silico splice models predict that c.686 G>T may damage the natural splice donor site in intron 12, which may cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of the c.686 G>T change in this individual is unknown. If c.686 G>T does not alter splicing, it will result in the R229L missense change. The R229L 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues (G223E, G230D) have been reported in the Human Gene Mutation Database in association with Alport syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret c.686 G>T as a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV001141281 SCV001301616 uncertain significance Alport syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.