ClinVar Genomic variation as it relates to human health

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.87). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000379845). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 25457163 , 33527515). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22574627 , 24374867 , 24628545 , 25457163 , 31051113 , 33353976 , 33527515). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Affects a glycine residue in a Gly-X-Y motif in the triple-helical region of the COL4A1 gene, where the majority of pathogenic missense variants occur and is predicted to disrupt normal protein folding and function (HGMD); 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: 25457163, 28098148, 24628545, 30837194, 31051113, 33527515, 31848469, 16107487, 17938367, 23394911)

The c.2317G>A (p.G773R) alteration is located in coding exon 30 of the COL4A1 gene. This alteration results from a G to A substitution at nucleotide position 2317, causing the glycine (G) at amino acid position 773 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation and has been reported as heterozygous in multiple individuals with features consistent with COL4A1-related disorder (Deml, 2014; Colin, 2014; Slavotinek, 2015; Hausman-Kedem, 2021). Another alteration that causes the same amino acid change c.2317G>C (p.G773R) has also been detected in two related individuals with clinical features consistent with COL4A1-related disorder (Shah, 2012). This amino acid position is highly conserved in available vertebrate species. The p.G773 amino acid is located within the triple-helical domain of the collagen IV alpha 1 chain, and this alteration affects one of the highly conserved glycine residues in the Gly-X-Y motif that make up this domain (Ramshaw, 1998). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

The observed stop gained c.6226G>T (p.Gly2076Ter) variant in F8 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Gly2076Ter variant is absent in gnomAD Exomes. This variant has not been submitted to the ClinVar database. Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. The reference amino acid of p.Gly2076Ter in F8 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal (p.Gly2076Ter) in the F8 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in F8 gene have been previously reported to be disease causing (Wang et al., 2022). Additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic.

The COL4A1 c.2317G>A variant is predicted to result in the amino acid substitution p.Gly773Arg. This variant has been reported de novo in multiple individuals with clinical features consistent with COL4A1-related disorders (Deml et al. 2014. PubMed ID: 24628545; Slavotinek et al. 2015. PubMed ID: 25457163; Hausman-Kedem et al. 2021. PubMed ID: 33527515; Lenassi et al. 2021. PubMed ID: 31848469; PreventionGenetics, internal data). The p.Gly348Asp variant affects a glycine residue in the conserved triple helical domain, where substitutions of the glycine are usually pathogenic (Zagaglia et al. 2018. PubMed ID: 30413629). This variant has not been reported in a large population database, indicating this variant is rare and has been consistently interpreted as pathogenic and likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/379845/). Taken together, this variant is interpreted as pathogenic.