Submissions for variant NM_033380.3(COL4A5):c.3197G>T (p.Gly1066Val)

dbSNP: rs104886221

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000991631	SCV001143252	pathogenic	not provided	2018-09-14	criteria provided, single submitter	clinical testing	The variant disrupts a glycine residue in the canonical Gly-X-Y repeats of the triple helix domain, which are required for stability and structure of this protein. Therefore it is expected to severely affect the function of the protein. Found in at least one symptomatic patient, and not found in general population data.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000991631	SCV002229371	pathogenic	not provided	2021-08-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine with valine at codon 1066 of the COL4A5 protein (p.Gly1066Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with COL4A5-related conditions. ClinVar contains an entry for this variant (Variation ID: 804587). 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 variant disrupts the p.Gly1066 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 11223851, 8940267, Invitae), which suggests that this may be a clinically significant amino acid residue. 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).
Fulgent Genetics, Fulgent Genetics	RCV002488085	SCV002793730	pathogenic	X-linked Alport syndrome	2021-12-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004749578	SCV005360998	likely pathogenic	COL4A5-related disorder	2024-03-07	no assertion criteria provided	clinical testing	The COL4A5 c.3197G>T variant is predicted to result in the amino acid substitution p.Gly1066Val. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. The p.Gly1066 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/). Alternate nucleotide changes affecting the same amino acid (p.Gly1066Ser, p.Gly1066Arg, p.Gly1066Ala) have been reported to be pathogenic for Alport syndrome (Martin et al. 1998. PubMed ID: 9848783; Knebelmann et al. 1996. PubMed ID: 8940267; Barker et al. 2001. PubMed ID: 11223851). This variant is interpreted as likely pathogenic.