ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.4001G>A (p.Gly1334Glu)

gnomAD frequency: 0.00001  dbSNP: rs375290088
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001950918 SCV002237274 pathogenic not provided 2023-06-23 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1334 of the COL4A3 protein (p.Gly1334Glu). This variant is present in population databases (rs375290088, gnomAD 0.007%). This missense change has been observed in individuals with autosomal dominant and recessive COL4A3-related conditions (PMID: 11134255, 26138234). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1455985). 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. Experimental studies have shown that this missense change affects COL4A3 function (PMID: 24262798). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002271709 SCV002555997 pathogenic Autosomal recessive Alport syndrome 2022-06-20 criteria provided, single submitter clinical testing Variant summary: COL4A3 c.4001G>A (p.Gly1334Glu) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249558 control chromosomes (gnomAD and publication data). c.4001G>A has been reported in the literature in multiple individuals affected with Alport Syndrome or familial microscopic hematuria due to thin basement membrane nephropathy, and this variant segregated with the disease (Heidet_2001, Papazachariou_2014, Stefanou_2015). These data indicate that the variant is very likely to be associated with disease. Functional studies report this variant showed retention of mutant collagens and differential activation of the unfolded protein response cascade (Pieri_2014, Papazachariou_2014). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV001950918 SCV002588261 pathogenic not provided 2022-10-19 criteria provided, single submitter clinical testing Observed in the heterozygous state in multiple individuals with focal segmental glomerulosclerosis and thin basement membrane nephropathy in published literature (Voskarides et al., 2008; Pierides et al., 2009); Published functional studies demonstrate defective collagen trafficking and possible ER stress-related apoptosis (Pieri et al., 2014); 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 (gnomAD); 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: 18439107, 28977688, 26138234, 18661361, 19525337, 30099615, 25514610, 11134255, 19357112, 24262798, 33718859, 24077912, 10752524)
Fulgent Genetics, Fulgent Genetics RCV002497879 SCV002809701 pathogenic Autosomal dominant Alport syndrome; Autosomal recessive Alport syndrome; Benign familial hematuria 2022-02-16 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001950918 SCV003916255 pathogenic not provided 2023-03-01 criteria provided, single submitter clinical testing COL4A3: PM1:Strong, PP1:Strong, PM2, PS4:Moderate, PS3:Supporting
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV003992591 SCV004809600 pathogenic Alport syndrome 3b, autosomal recessive 2024-04-04 criteria provided, single submitter clinical testing

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