ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.2452G>A (p.Gly818Arg)

gnomAD frequency: 0.00001  dbSNP: rs868002181
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000517367 SCV000612944 pathogenic not provided 2016-03-25 criteria provided, single submitter clinical testing
GeneDx RCV000517367 SCV001982067 pathogenic not provided 2021-09-20 criteria provided, single submitter clinical testing Reported as a single heterozygous variant in several unrelated individuals with features suggestive of Alport syndrome (Gast et al., 2016; Sen et al., 2017; Connaughton et al., 2019; Yao et al., 2019); of note, one individual inherited this variant from an unaffected parent; Reported with a pathogenic variant on the opposite allele (in trans) with a second COL4A3 variant in an individual with features suggestive of Alport syndrome (Storey et al., 2013); Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A3 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (Stenson et al., 2014; Jais et al., 2000); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28780565, 24077912, 10752524, 24052634, 30773290, 26346198, 30647093)
Myriad Genetics, Inc. RCV000668107 SCV002060243 uncertain significance Autosomal recessive Alport syndrome 2021-11-10 criteria provided, single submitter clinical testing NM_000091.4(COL4A3):c.2452G>A(G818R) is a missense variant classified as a variant of uncertain significance in the context of COL4A3-related Alport syndrome. G818R has been observed in cases with relevant disease (PMID: 30773290, 28780565, 26346198, 24052634). Functional assessments of this variant are not available in the literature. G818R has been observed in population frequency databases (gnomAD: NFE 0.003%). In summary, there is insufficient evidence to classify NM_000091.4(COL4A3):c.2452G>A(G818R) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Invitae RCV000517367 SCV002275128 pathogenic not provided 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 818 of the COL4A3 protein (p.Gly818Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Alport syndrome (PMID: 24052634, 26346198, 30586318, 30647093, 30773290; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 447169). 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) performed at Invitae indicates that this missense variant is expected to disrupt COL4A3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity Omics RCV000517367 SCV003819251 pathogenic not provided 2022-09-27 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003419893 SCV004107208 likely pathogenic COL4A3-related condition 2022-12-20 criteria provided, single submitter clinical testing The COL4A3 c.2452G>A variant is predicted to result in the amino acid substitution p.Gly818Arg. This variant was reported in the compound heterozygous state in an individual with Alport syndrome (Patient 11, Storey et al. 2013. PubMed ID: 24052634). This variant was also reported, along with another variant in COL4A3 (phase not noted) in siblings with likely Alport disease and likely hereditary nephritis (Family F2, Gast et al. 2016. PubMed ID: 26346198) and in an individual with glomerulopathy (Supplemental Table 7, Patient ID: CKD152, Groopman et al. 2019. PubMed ID: 30586318). This variant was also reported with a COL4A4 missense variant in an individual with Alport syndrome and both were maternally inherited (Supplemental Table 2, Patient 7, Sen et al. 2017. PubMed ID: 28780565). Of note, for that patient the variant was reported to track with disease in four affected and two unaffected individuals. This variant was also reported in the heterozygous state in an individual with hematuria (Family ID: B2347, Individual ID: 17, Connaughton et al. 2019. PubMed ID: 30773290) and in an individual with steroid-resistant nephrotic syndrome, undescended testes, and a penile anomaly (Supplemental Table 2, Patient 64, Sen et al. 2017. PubMed ID: 28780565). Of note the second patient listed also carried a de novo WT1 variant and the COL4A3 variant was inherited from an unaffected father. This variant was also reported in the heterozygous state in an individual with focal segmental glomerulosclerosis (FSGF) (Patient 7215, Family F23, Yao et al. 2019. PubMed ID: 30647093). This variant is reported in 0.0028% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-228145686-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance, to likely pathogenic, to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/447169/). The p.Gly818Arg residue is located in the conserved triple helical domain, where substitutions of the glycine are usually pathogenic (UniProt residues 43-1438, Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK21582/). Taken together, this variant is interpreted as likely pathogenic.
Gharavi Laboratory, Columbia University RCV000517367 SCV000809252 likely pathogenic not provided 2018-09-16 no assertion criteria provided research
Yale Center for Mendelian Genomics, Yale University RCV001849395 SCV002106600 likely pathogenic Autosomal dominant Alport syndrome 2019-02-14 no assertion criteria provided literature only

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