Submissions for variant NM_033380.3(COL4A5):c.3427G>A (p.Gly1143Ser)

dbSNP: rs104886228

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Gharavi Laboratory, Columbia University	RCV000681895	SCV000809374	likely pathogenic	not provided	2018-09-16	criteria provided, single submitter	research
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000021509	SCV000889954	pathogenic	X-linked Alport syndrome	2017-02-23	criteria provided, single submitter	clinical testing
Invitae	RCV000681895	SCV001222920	pathogenic	not provided	2023-01-26	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 24630). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL4A5. 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 COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) 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 COL4A5 protein function. This missense change has been observed in individual(s) with X-linked dominant Alport syndrome (PMID: 7969679). It has also been observed to segregate with disease in related individuals. 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 1143 of the COL4A5 protein (p.Gly1143Ser).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000021509	SCV001429110	likely pathogenic	X-linked Alport syndrome	2017-12-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000681895	SCV001982247	pathogenic	not provided	2021-09-28	criteria provided, single submitter	clinical testing	Reported in multiple individuals with Alport syndrome belonging to a single family in published literature (Renieri et al., 1994; Renieri et al., 1996); however, data is limited; Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A5 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (Stenson et al., 2014; Jais et al., 2000); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 25525159, 8651296, 24077912, 7969679)
CeGaT Center for Human Genetics Tuebingen	RCV000681895	SCV002564125	pathogenic	not provided	2020-09-01	criteria provided, single submitter	clinical testing
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000021509	SCV002764652	pathogenic	X-linked Alport syndrome	2022-03-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000021509	SCV002778689	pathogenic	X-linked Alport syndrome	2022-05-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003894817	SCV004715571	pathogenic	COL4A5-related condition	2023-12-12	criteria provided, single submitter	clinical testing	The COL4A5 c.3427G>A variant is predicted to result in the amino acid substitution p.Gly1143Ser. This variant has been reported to be causative for X-linked Alport Syndrome (Renieri et al. 1994. PubMed ID: 7969679; Stapleton et al. 2019. PubMed ID: 31865346). The p.Gly1143Ser residue resides in the triple-helical region (residues 42 – 1456) of the COL4A5 protein (uniprot.org). The majority of pathogenic variants in COL4A5 substitute a glycine residue to a bulkier amino acid in the triple-helical domain (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.