ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.1855G>A (p.Gly619Arg) (rs773515249)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000681773 SCV001234379 uncertain significance not provided 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 619 of the COL4A3 protein (p.Gly619Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs773515249, ExAC 0.003%). This variant has been observed in individual(s) with autosomal recessive Alport syndrome (PMID: 24633401, 25596306). ClinVar contains an entry for this variant (Variation ID: 522482). This variant has been reported to have conflicting or insufficient data to determine the effect on COL4A3 protein function (PMID: 31306228). 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. 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.
Medical Genetics, University of Parma RCV001089917 SCV001245150 pathogenic Alport syndrome 3, autosomal dominant; Benign familial hematuria 2020-03-11 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000625624 SCV001427123 likely pathogenic Alport syndrome 3, autosomal dominant 2018-07-30 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_000091.4(COL4A3):c.1855G>A, has been identified in exon 26 of 52 of the COL4A3 gene. The variant is predicted to result in a major amino acid change from glycine to arginine at position 619 of the protein, NP_000082.2(COL4A3):p.(Gly619Arg). The glycine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the collagen triple-helical domain. 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 0.0008% (2 heterozygotes). The variant has previously been reported in families with either autosomal recessive or dominant Alport syndrome (ClinVar, Moriniere, V., et al. (2014), Oka, M., et al. (2014), Xie, J., et al. (2014)). In addition, it has been described as a VUS in a patient with steroid-resistant nephrotic syndrome with focal segmental glomerulosclerosis (Sen, E., et al. (2017)). Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC.
Precision Medicine Center,Zhengzhou University RCV001391170 SCV001593068 likely pathogenic Alport syndrome, autosomal recessive criteria provided, single submitter research PM1:Located in a mutational hot spot PM2:not found in gnomAD PP2:Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease PP3:Multiple lines of computational evidence support a deleterious effect on the gene or gene product
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000625624 SCV000746125 likely pathogenic Alport syndrome 3, autosomal dominant 2017-09-18 no assertion criteria provided clinical testing
Gharavi Laboratory,Columbia University RCV000681773 SCV000809235 likely pathogenic not provided 2018-09-16 no assertion criteria provided research

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