ClinVar Genomic variation as it relates to human health

The c.4147G>A (p.G1383R) alteration is located in exon 44 (coding exon 43) of the COL4A2 gene. This alteration results from a G to A substitution at nucleotide position 4147, causing the glycine (G) at amino acid position 1383 to be replaced by an arginine (R). The alteration is not observed in healthy cohorts:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the COL4A2 c.4147G>A alteration was not observed among 5,910 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The altered amino acid is conserved throughout evolution:_x000D_ The p.G1383 amino acid position is completely conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ The p.G1383R amino acid is located within one of the G-X-Y repeats of the triple helical domain, which is essential for the normal folding of the triple helix. Most COL4A2 mutations in humans are substitutions of these conserved G residues and have a dominant negative effect upon protein function (reviewed in Yoneda, 2012 and Varbeek, 2012). The alteration is predicted deleterious by in silico models:_x000D_ The p.G1383R alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as likely pathogenic.

Not observed 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: 24001601, 26708157, 25719457, 24390199, 22333902, 22209247, 22209246, 30413629)

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1383 of the COL4A2 protein (p.Gly1383Arg). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as 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 COL4A2 protein function. ClinVar contains an entry for this variant (Variation ID: 208773). This missense change has been observed in individual(s) with clinical features of COL4A2-related conditions (PMID: 30413629). In at least one individual the variant was observed to be de novo.