Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV001767392 | SCV001998210 | uncertain significance | not provided | 2024-12-10 | criteria provided, single submitter | clinical testing | Reported in the heterozygous state in multiple affected individuals with hearing loss, pigmented retinopathy and normal renal function within a single family in published literature (PMID: 30881523); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease; This variant is associated with the following publications: (PMID: 30881523) |
| Fulgent Genetics, |
RCV005005277 | SCV002775166 | uncertain significance | Autosomal dominant Alport syndrome; Hematuria, benign familial, 2; Alport syndrome 3b, autosomal recessive | 2024-03-12 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001767392 | SCV003261767 | uncertain significance | not provided | 2024-03-19 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1076 of the COL4A3 protein (p.Pro1076Leu). This variant is present in population databases (rs200984988, gnomAD 0.02%). This missense change has been observed in individual(s) with hearing loss and eye abnormalities, but without hematuria (PMID: 30881523). ClinVar contains an entry for this variant (Variation ID: 1310278). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A3 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, |
RCV003987902 | SCV004804502 | uncertain significance | not specified | 2024-01-12 | criteria provided, single submitter | clinical testing | Variant summary: COL4A3 c.3227C>T (p.Pro1076Leu) results in a non-conservative amino acid change located in the Collagen triple helix repeat domain (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 7.6e-05 in 249500 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (7.6e-05 vs 0.0014), allowing no conclusion about variant significance. c.3227C>T has been reported in the literature in several heterozygous family members affected with hearing loss and ocular abnormalities, however none of the carriers were affected with hematuria, proteinuria, or impaired renal function (e.g., Xia_2019). This report therefore does not provide unequivocal conclusions about association of the variant with Alport Syndrome, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36013122, 33851121, 30881523). ClinVar contains an entry for this variant (Variation ID: 1310278). Based on the evidence outlined above, the variant was classified as uncertain significance. |