Submissions for variant NM_001845.6(COL4A1):c.1801G>A (p.Gly601Ser)

dbSNP: rs1064794777

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480157	SCV000569924	pathogenic	not provided	2024-11-12	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; PMID: 22522439, 23225343); 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: 30413629, 22522439, 23225343, 35699195)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000480157	SCV003473263	pathogenic	not provided	2023-08-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 601 of the COL4A1 protein (p.Gly601Ser). 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). 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 420899). This missense change has been observed in individual(s) with COL4A1-related conditions (PMID: 30413629). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency).
Neuberg Centre For Genomic Medicine, NCGM	RCV004584728	SCV005073864	pathogenic	Brain small vessel disease 1 with or without ocular anomalies		criteria provided, single submitter	clinical testing	The observed missense variant c.1801G>A (p.Gly601Ser) in COL4A1 gene has been reported previously in a triple helix domain in heterozygous state in two individuals affected with COL4A1 related disorder (Zagaglia S et al. 2018). The p.Gly601Ser variant is absent in gnomAD Exomes. 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 (Shoulders MD et al. 2009). In COL4A1 variants affecting these glycine residues are significantly enriched in individuals with disease (Dalgleish R. et al. 1997). This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic. The amino acid change p.Gly601Ser in COL4A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence predicts a damaging effect on protein structure and function for this variant (Polyphen - probably damaging; Sift - damaging; Mutation Taster - disease causing). The amino acid Gly at position 601 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.