Submissions for variant NM_033380.3(COL4A5):c.3508G>A (p.Gly1170Ser)

gnomAD frequency: 0.00001  dbSNP: rs104886237

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382251	SCV001580930	pathogenic	not provided	2024-01-21	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 1170 of the COL4A5 protein (p.Gly1170Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alport syndrome (PMID: 10561141, 30577881; Invitae). ClinVar contains an entry for this variant (Variation ID: 24638). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000021517	SCV001752685	pathogenic	X-linked Alport syndrome	2021-06-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001382251	SCV001823400	pathogenic	not provided	2022-11-08	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 (Stenson et al., 2014; Jais et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19919694, 26346198, 10561141, 25869794, 30577881, 30647093, 32703181, 33712733)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000021517	SCV002507099	uncertain significance	X-linked Alport syndrome	2022-05-04	criteria provided, single submitter	curation	The heterozygous p.Gly1170Ser variant in COL4A5 was identified by our study in 1 individual with X-linked Alport syndrome. The variant has been reported in 11 individuals of unknown, European, and Japanese ethnicity with X-linked Alport syndrome (PMID: 10561141, 24359068, 18616531, 26346198, 30647093, 30577881, 25869794) and has been identified in 0.001% (1/77236) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs104886237). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 24638) as pathogenic by Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare, and as Moderate by Research and Development, ARUP Laboratories. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_moderate, PP3 (Richards 2015).
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000021517	SCV002577408	pathogenic	X-linked Alport syndrome	2022-06-24	criteria provided, single submitter	clinical testing	PS4, PM1, PM2, PM5, PP2, PP3, PP5
Institute of Human Genetics, University of Leipzig Medical Center	RCV000021517	SCV002587106	pathogenic	X-linked Alport syndrome	2022-10-24	criteria provided, single submitter	clinical testing	This variant was identified as hemizygous._x000D_ Criteria applied: PM5_STR, PS4_MOD, PM1, PM2_SUP, PP3, PP4
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000021517	SCV002758779	pathogenic	X-linked Alport syndrome		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000021517	SCV004813632	pathogenic	X-linked Alport syndrome	2024-02-07	criteria provided, single submitter	clinical testing	Variant summary: COL4A5 c.3508G>A (p.Gly1170Ser) results in a non-conservative amino acid change located in the collagen triple helix repeat region of the encoded protein sequence. Alterations of glycine residues within the collagen triple-helix are common mechanisms of disease. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-06 in 174685 control chromosomes (gnomAD). c.3508G>A has been reported in the literature in multiple individuals affected with X-Linked Recessive Alport Syndrome 1 (e.g. Pont-Kingdon_2009, Zhang_2018, Kim_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37100867, 19919694, 30577881). ClinVar contains an entry for this variant (Variation ID: 24638). Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000021517	SCV005086708	pathogenic	X-linked Alport syndrome	2022-09-02	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). Dominant negative is caused mostly by glycine substitutions that affect the conformation of the protein, and loss of function can be caused by either protein truncating or missense variants (PMIDs: 24046192, 12028435). (I) 0110 - This gene is associated with X-linked dominant disease. Males are typically more severely affected than females (PMID: 19965530). (I) 0115 - Variants in this gene are known to have variable expressivity. There is intrafamilial variability among affected carrier females, possibly due to variable X-inactivation (PMID: 14514738). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0253 - This variant is hemizygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 1 heterozygote, 0 homozygotes, 0 hemizygotes). (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 the well-established functional triple helical domain. The residue affected is the Gly of the Gly-X-Y repeat (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals with Alport syndrome, and consistently classified as pathogenic by diagnostic laboratories in ClinVar (PMIDs: 24359068, 26346198, 30577881, 30647093, 33712733). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000021517	SCV005382599	pathogenic	X-linked Alport syndrome	2019-06-03	criteria provided, single submitter	clinical testing	This missense variant (c.3508G>A; p.Gly1170Ser) has not been observed in population databases (gnomAD), although it has been reported in the literature (PMID 10521141, PMID 26346198). Variant prediction programs suggest a deleterious effect, although no functional studies have been published. It was found in an affected male wtih a clinical diagnosis of Alport Syndrome, and a similarly affected male relative carries the same variant.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000021517	SCV000925796	pathogenic	X-linked Alport syndrome	2018-11-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003934847	SCV004749821	pathogenic	COL4A5-related disorder	2024-09-27	no assertion criteria provided	clinical testing	The COL4A5 c.3508G>A variant is predicted to result in the amino acid substitution p.Gly1170Ser. The p.Gly1170 residue resides in the triple-helical region (residues 42 – 1456) of the COL4A5 protein (uniprot.org), where substitutions of the glycine (Gly) residue are usually pathogenic (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant has been reported to be pathogenic for COL4A5 nephropathy (see for example, male and female with focal segmental glomerulosclerosis in Gast et al. 2016. PubMed ID: 26346198; female with mild Alport syndrome in Inoue et al. 1999. PubMed ID: 10561141; female with focal segmental glomerulosclerosis in Schrezenmeier et al. 2021. PubMed ID: 33712733). This variant is reported in 0.0013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.