Submissions for variant NM_001845.6(COL4A1):c.634G>A (p.Gly212Ser)

dbSNP: rs878853070

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000224555	SCV001780950	pathogenic	not provided	2022-03-21	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 (Stenson et al., 2014; Weng et al., 2012; Yoneda et al., 2013); Not observed at significant frequency 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: 30181649, 31172278, 32499604, 24077912, 22522439, 23225343)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000224555	SCV003240881	pathogenic	not provided	2023-06-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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). 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) performed at Invitae indicates that this missense variant is expected to disrupt COL4A1 protein function. ClinVar contains an entry for this variant (Variation ID: 235568). This missense change has been observed in individual(s) with clinical features of COL4A1-related conditions (PMID: 30181649). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 212 of the COL4A1 protein (p.Gly212Ser).
Duke University Health System Sequencing Clinic, Duke University Health System	RCV003223398	SCV003919020	pathogenic	Brain small vessel disease 1 with or without ocular anomalies	2023-04-20	criteria provided, single submitter	research
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224555	SCV000281250	uncertain significance	not provided	2016-04-29	flagged submission	clinical testing	Converted during submission to Uncertain significance.
Eye Genetics Research Group, Children's Medical Research Institute	RCV001200033	SCV001370525	likely pathogenic	Anterior segment dysgenesis	2020-03-31	no assertion criteria provided	clinical testing