Submissions for variant NM_001845.6(COL4A1):c.2317G>A (p.Gly773Arg)

dbSNP: rs672601347

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000437521	SCV000517312	pathogenic	not provided	2021-11-22	criteria provided, single submitter	clinical testing	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)
Ambry Genetics	RCV000623415	SCV000741072	pathogenic	Inborn genetic diseases	2023-08-10	criteria provided, single submitter	clinical testing	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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000437521	SCV001447290	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
3billion	RCV002283479	SCV002572869	pathogenic	Brain small vessel disease 1 with or without ocular anomalies	2022-09-01	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV002502498	SCV002804545	pathogenic	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome; Brain small vessel disease 1 with or without ocular anomalies; Hemorrhage, intracerebral, susceptibility to; Retinal arterial tortuosity; Microangiopathy and leukoencephalopathy, pontine, autosomal dominant	2021-07-14	criteria provided, single submitter	clinical testing
Molecular Medicine, University of Pavia	RCV002283479	SCV004022318	likely pathogenic	Brain small vessel disease 1 with or without ocular anomalies	2023-07-28	criteria provided, single submitter	research
Neuberg Centre For Genomic Medicine, NCGM	RCV002283479	SCV005374826	pathogenic	Brain small vessel disease 1 with or without ocular anomalies		criteria provided, single submitter	clinical testing	The observed missense c.2317G>A (p.Gly773Arg) variant in COL4A1 gene has been reported in multiple individuals affected with COL4A1-related disorders (Shah et al., 2012; Colin et al., 2014; Deml et al., 2014; Slavotinek et al., 2015; Labelle-Dumais et al., 2019; Hausman-Kedem et al., 2021). This variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Gly773Arg in COL4A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 773 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000437521	SCV005835495	pathogenic	not provided	2024-03-20	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 773 of the COL4A1 protein (p.Gly773Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with COL4A1-related conditions (PMID: 22574627, 25457163, 33527515). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 379845). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004739722	SCV005357338	pathogenic	COL4A1-related disorder	2024-05-20	no assertion criteria provided	clinical testing	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.