Submissions for variant NM_033380.3(COL4A5):c.1001G>A (p.Gly334Asp)

dbSNP: rs104886093

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002032540	SCV002234378	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 aspartic acid at codon 334 of the COL4A5 protein (p.Gly334Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Alport syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 1184578). 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 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). This variant disrupts the p.Gly334 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been observed in individuals with COL4A5-related conditions (PMID: 19728970, 24304881), which suggests that this may be a clinically significant amino acid residue.
GeneDx	RCV002032540	SCV002574637	pathogenic	not provided	2022-09-02	criteria provided, single submitter	clinical testing	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 (HGMD; Jais et al., 2000); 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: 10752524, 34758253)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001542720	SCV002767919	pathogenic	X-linked Alport syndrome	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with X-linked Alport syndrome 1 (MIM#301050). Glycine changes in the G-X-Y repeat within the triple helix of a collagen domain are known to have a dominant-negative effect (PMID: 12028435). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Male patients tend to be more severly affected than females (PMID: 19965530). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in a well-established functional domain. The variant affects the glycine residue in a Gly-X-Y motif of the collagen triple helix repeat (PDB). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Alternative changes at the same residue to valine and serine have previously been reported as pathogenic in individuals with X-linked Alport syndrome 1 (MIM#301050) (ClinVar, HGMD, LOVD). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. The variant has previously been classified as pathogenic in a single report (LOVD). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genomics England Pilot Project, Genomics England	RCV001542720	SCV001760499	likely pathogenic	X-linked Alport syndrome		no assertion criteria provided	clinical testing