Submissions for variant NM_000091.5(COL4A3):c.2434G>A (p.Gly812Ser)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003076851	SCV003453978	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 812 of the COL4A3 protein (p.Gly812Ser). 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 variant has not been reported in the literature in individuals affected with COL4A3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003988048	SCV004804503	uncertain significance	not specified	2024-01-12	criteria provided, single submitter	clinical testing	Variant summary: COL4A3 c.2434G>A (p.Gly812Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 178112 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (5.6e-05 vs 0.0014), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2434G>A in individuals affected with Alport Syndrome, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2146778). Gly812 is located at non-collagenous boundary, thus the effect of Gly812Ser is not clear (PMID 34400539). Based on the evidence outlined above, the variant was classified as VUS.
GeneDx	RCV003076851	SCV005396571	uncertain significance	not provided	2024-05-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A3 gene.; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV005019623	SCV005651303	uncertain significance	Autosomal dominant Alport syndrome; Hematuria, benign familial, 2; Alport syndrome 3b, autosomal recessive	2024-06-04	criteria provided, single submitter	clinical testing