Submissions for variant NM_033380.3(COL4A5):c.2605G>A (p.Gly869Arg)

dbSNP: rs104886189

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000311568	SCV000329767	pathogenic	not provided	2016-09-02	criteria provided, single submitter	clinical testing	The G869R pathogenic variant in the COL4A5 gene has been reported previously in multiple unrelated individuals with X-linked Alport syndrome (Boye et al., 1995; Knebelman et al., 1996; Plant et al., 1999). The G869R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G869R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G869R as a pathogenic variant.
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000021422	SCV000747762	pathogenic	X-linked Alport syndrome	2017-12-05	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000021422	SCV001164380	likely pathogenic	X-linked Alport syndrome	2018-12-03	criteria provided, single submitter	research	The hemizygous p.Gly869Arg variant in COL4A5 was identified by our study in one individual with X-linked Alport syndrome. This variant was absent from large population studies and computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Trio exome analysis showed this variant to be de novo in one individual reported in the literature (PMID: 8940267). The p.Gly869Arg variant in COL4A5 has been reported in ten additional individuals with Alport syndrome (PMID: 8651296, 7599631, 9848783). This variant has also been reported pathogenic in ClinVar (Variation ID: 24543). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM6, PP3 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000311568	SCV001214001	pathogenic	not provided	2024-09-16	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 869 of the COL4A5 protein (p.Gly869Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alport syndrome (PMID: 7599631, 30577881). This variant is also known as c.2808G>A. ClinVar contains an entry for this variant (Variation ID: 24543). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
3billion, Medical Genetics	RCV000021422	SCV002059127	pathogenic	X-linked Alport syndrome	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000024543, PS1_S). A different missense change at the same codon has been reported to be associated with COL4A5 related disorder (ClinVar ID: VCV000807394, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.978, 3CNET: 0.973, PP3_P). A missense variant is a common mechanism associated with Alport syndrome 1 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000021422	SCV002767917	pathogenic	X-linked Alport syndrome	2022-03-31	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, caused by missense variants mostly glycine substitutions that affect the conformation of the protein, and loss of function, caused by either protein truncating or missense variants, are known mechanisms of disease in this gene and are associated with Alport syndrome (MIM#301050) (PMIDs: 24046192, 12028435). (I) 0110 - This gene is associated with X-linked dominant disease, with males usually affected more severely 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 arginine. (I) 0251 - This variant is heterozygous. (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 the well-established triple helical G-X-Y repeat region, and affects a glycine residue (DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Gly869Val) has been previously reported as pathogenic by a clinical laboratory in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as pathogenic, and has been observed in many hemizygous or heterozygous individuals with Alport syndrome (ClinVar, PMIDs: 27627812, 23144074). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000021422	SCV002806615	pathogenic	X-linked Alport syndrome	2024-04-20	criteria provided, single submitter	clinical testing
Watson Genetic Lab	RCV000021422	SCV005046906	pathogenic	X-linked Alport syndrome		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000021422	SCV005077015	pathogenic	X-linked Alport syndrome	2024-04-23	criteria provided, single submitter	clinical testing	Variant summary: COL4A5 c.2605G>A (p.Gly869Arg) results in a non-conservative amino acid change located within the triple-helical region (UniProt) of the encoded protein sequence. This missense variant disrupts a critical glycine residue at position 1 of a Gly-X-Y repeat in the collagenous domain of the collagen IV alpha 5 chain, and variants affecting these glycine residues are significantly enriched in individuals with Alport syndrome (PMID: 33854215). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182139 control chromosomes. c.2605G>A has been reported in the literature in individuals affected with Alport Syndrome 1, X-Linked Recessive (example, Connaughton_2019, Hashimura_2014, Ma_2011). These data indicate that the variant is 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: 30773290, 24304881, 21505094). ClinVar contains an entry for this variant (Variation ID: 24543). Based on the evidence outlined above, the variant was classified as pathogenic.
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328141	SCV001449304	pathogenic	Alport syndrome	2019-09-13	no assertion criteria provided	clinical testing	This individual is heterozygous for the c.2605G>A variant in the COL4A5 gene, which results in the amino acid substitution of glycine to arginine at residue 869, p.(Gly869Arg). This substitution affects one of the invariant glycine residues within the triple helical domain. This variant has been reported in numerous individuals with Alport syndrome (Knebelmann B et al 1996 Am J Hum Genet 59: 1221-1232; Ma et al 2011 Nephrol Dial Transplant 26: 4003-4010; Strasser et al 2012 Nephrol Dial Transplant 27: 4236-4240; Alport (COL4A5) Database: http://www.arup.utah.edu/database/ALPORT/ALPORT_display.php). The c.2605G>A variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP). This variant is considered to be pathogenic according to the ACMG guidelines (Evidence used: PM1_Strong, PS4).
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328145	SCV001449309	pathogenic	Atypical hemolytic-uremic syndrome	2018-10-25	no assertion criteria provided	clinical testing	This patient is hemizygous for the c.2605G>A (p.Gly869Arg) variant in the COL4A5 gene. This variant has been reported to be associated with Alport syndrome (Strasser et al Nephrol Dial Transplant (2012) 27: 4236-4240). In silico analysis (Alamutv2.4) using Align GVGD, PolyPhen2, SIFT and Mutation taster all predict that this variant is likely to be pathogenic. In addition, p.Gly869 is a highly conserved amino acid within the triple helix domain. Glycine residues, in this domain, are important for the steric arrangement of the collagen chains (Knebelmann B et al. Am J Hum Genet 1996; 59: 1221-1232).
Natera, Inc.	RCV000021422	SCV002083648	pathogenic	X-linked Alport syndrome	2018-01-09	no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV001849275	SCV002106604	pathogenic	Autosomal dominant Alport syndrome	2019-02-14	no assertion criteria provided	literature only