Submissions for variant NM_001845.6(COL4A1):c.922G>A (p.Gly308Arg)

gnomAD frequency: 0.00003  dbSNP: rs370677625

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478856	SCV000572806	uncertain significance	not provided	2019-12-18	criteria provided, single submitter	clinical testing	Observed in 0.0016% (4/251476 alleles) in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000478856	SCV002188968	likely pathogenic	not provided	2024-11-22	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 308 of the COL4A1 protein (p.Gly308Arg). This variant is present in population databases (rs370677625, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with COL4A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 423149). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL4A1 protein function with a positive predictive value of 95%. 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002525922	SCV003536397	uncertain significance	Inborn genetic diseases	2023-10-06	criteria provided, single submitter	clinical testing	The c.922G>A (p.G308R) alteration is located in exon 17 (coding exon 17) of the COL4A1 gene. This alteration results from a G to A substitution at nucleotide position 922, causing the glycine (G) at amino acid position 308 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005010396	SCV005632466	likely 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	2024-05-23	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV003762750	SCV000607212	not provided	COL4A1-related disorder		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.