ClinVar Miner

Submissions for variant NM_000092.5(COL4A4):c.5045G>A (p.Arg1682Gln)

gnomAD frequency: 0.00010  dbSNP: rs368404711
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000516925 SCV000612975 uncertain significance not specified 2017-06-07 criteria provided, single submitter clinical testing
Invitae RCV000681727 SCV001415599 pathogenic not provided 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1682 of the COL4A4 protein (p.Arg1682Gln). This variant is present in population databases (rs368404711, gnomAD 0.2%). This missense change has been observed in individuals with hematuria and thin basement membrane nephropathy (PMID: 17216251, 26809805, 27859054). ClinVar contains an entry for this variant (Variation ID: 447192). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A4 protein function. This variant disrupts the p.Arg1682 amino acid residue in COL4A4. Other variant(s) that disrupt this residue have been observed in individuals with COL4A4-related conditions (PMID: 21897443), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000681727 SCV001986311 uncertain significance not provided 2021-03-18 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with hematuria, proteinuria, or kidney disease in the published literature, some of these individuals also had a variant in the COL4A3 gene (Rana et al., 2007; Fallerini et al., 2017; Bullich et al., 2018); This variant is associated with the following publications: (PMID: 27859054, 17216251, 29801666, 26809805)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000681727 SCV002051496 uncertain significance not provided 2020-11-25 criteria provided, single submitter clinical testing PP3
PreventionGenetics, part of Exact Sciences RCV003419895 SCV004118207 uncertain significance COL4A4-related condition 2022-12-01 criteria provided, single submitter clinical testing The COL4A4 c.5045G>A variant is predicted to result in the amino acid substitution p.Arg1682Gln. This variant was reported in the heterozygous state in two individuals with thin basement membrane nephropathy (Rana et al. 2007. PubMed ID: 17216251; Weber et al. 2016. PubMed ID: 26809805). This variant was interpreted as likely pathogenic for autosomal dominant Alport syndrome based on ACMG criteria (Table S1, Furlano et al, 2021PubMed ID: 33838161). This variant was also reported in the heterozygous state along with a missense variant in COL4A3 in two individuals with Alport syndrome, with a proposed digenic inheritance (Fallerini et al. 2017. PubMed ID: 27859054; Table S3, Bullich. 2018. PubMed ID: 29801666). Of note, an affected sibling of the proband also carried the COL4A4 c.5045G>A (p.Arg1682Gln), but did not have the COL4A3 variant;. A nephew of the proband, who had proteinuria, was negative for both the COL4A4 c.5045G>A (p.Arg1682Gln) and the COL4A3 variant (Table 1, Fallerini et al. 2017. PubMed ID: 27859054). This variant is reported in 0.20% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-227872069-C-T) and has conflicting interpretations of pathogenicity in ClinVar ranging from uncertain to likely pathogenic (http://www.ncbi.nlm.nih.gov/clinvar/variation/447192). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Gharavi Laboratory, Columbia University RCV000681727 SCV000809180 likely pathogenic not provided 2018-09-16 no assertion criteria provided research

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