Submissions for variant NM_001845.6(COL4A1):c.2086G>A (p.Gly696Ser)

dbSNP: rs587780588

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000398907	SCV000330184	pathogenic	not provided	2020-11-06	criteria provided, single submitter	clinical testing	Reported in a 61 year-old female with new onset seizure and status epilepticus and previous history of ischemic and hemorrhagic brain lesions in the published literature (John et al., 2015); Not observed in large population cohorts (Lek et al., 2016); 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); 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: 32033901, 26362372, 31857254)
Baylor Genetics	RCV002247502	SCV001524247	pathogenic	Brain small vessel disease 1 with or without ocular anomalies	2019-08-23	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genetics Institute, Tel Aviv Sourasky Medical Center	RCV001391278	SCV001593229	pathogenic	Abnormal corpus callosum morphology; Intraventricular hemorrhage	2021-05-12	criteria provided, single submitter	clinical testing
Invitae	RCV000398907	SCV002238465	pathogenic	not provided	2022-12-20	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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 135653). This missense change has been observed in individual(s) with COL4A1-related conditions (PMID: 26362372, 31857254, 32033901). 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 696 of the COL4A1 protein (p.Gly696Ser).
Mendelics	RCV002247502	SCV000165988	likely pathogenic	Brain small vessel disease 1 with or without ocular anomalies	2013-02-08	no assertion criteria provided	clinical testing
Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University	RCV001030993	SCV000995063	likely pathogenic	Cerebral calcification; Intracranial hemorrhage	2019-04-17	no assertion criteria provided	curation	The identical mutation has been reported to cause late-onset intracranial hemorrhage. Congenital calcification and T2 high-intensity lesions in the cerebral white matter are compatible to the MRI features of previously reported cases.