ClinVar Miner

Submissions for variant NM_001845.6(COL4A1):c.868G>A (p.Gly290Arg)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV003179605 SCV003875865 uncertain significance Inborn genetic diseases 2023-02-23 criteria provided, single submitter clinical testing The c.868G>A (p.G290R) alteration is located in exon 16 (coding exon 16) of the COL4A1 gene. This alteration results from a G to A substitution at nucleotide position 868, causing the glycine (G) at amino acid position 290 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV003779620 SCV004626956 likely pathogenic not provided 2023-08-14 criteria provided, single submitter clinical testing This variant disrupts the triple helix domain of COL4A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A1 variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 COL4A1 protein function. ClinVar contains an entry for this variant (Variation ID: 2461073). This variant has not been reported in the literature in individuals affected with COL4A1-related conditions. This variant is present in population databases (rs757065258, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 290 of the COL4A1 protein (p.Gly290Arg).

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