Submissions for variant NM_000092.5(COL4A4):c.4394G>A (p.Gly1465Asp)

gnomAD frequency: 0.00004  dbSNP: rs533297350

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626596	SCV000747297	likely pathogenic	Hearing impairment; Myopia; Proteinuria; Hematuria; Hypertensive disorder	2017-01-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000673767	SCV000799008	uncertain significance	Autosomal recessive Alport syndrome	2018-04-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001868162	SCV002306481	pathogenic	not provided	2024-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1465 of the COL4A4 protein (p.Gly1465Asp). This variant is present in population databases (rs533297350, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of autosomal dominant Alport syndrome, autosomal recessive Alport syndrome, and basement membrane disease (PMID: 24033287, 26934356, 28632965, 34584596). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 523324). 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 COL4A4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV001328187	SCV002498602	uncertain significance	Alport syndrome	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change in COL4A4 is predicted to replace glycine with aspartic acid at codon 1465 (p.(Gly1465Asp)). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in the collagen IV NC1 domain. There is a moderate physicochemical difference between glycine and aspartic acid. The highest population minor allele frequency in gnomAD v2.1 is 0.04% (13/30,488 alleles) in the South Asian population, which is lower than the credible allele frequency for recessive Alport syndrome. This variant is almost always reported in cis with the likely pathogenic variant c.2320G>C, p.(Gly774Arg) in individuals and families with both dominant and recessive forms of Alport syndrome (PMID: 24033287, 26934356, 28632965, 29496980, 33048202, 33838161). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3.
Mendelics	RCV002248830	SCV002518752	pathogenic	Benign familial hematuria	2022-05-04	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000673767	SCV004048009	likely pathogenic	Autosomal recessive Alport syndrome		criteria provided, single submitter	clinical testing	The missense variant c.4394G>A(p.Gly1465Asp) in COL4A4 gene has been observed in heterozygous state in individual(s) with clinical features of autosomal dominant Alport syndrome, autosomal recessive Alport syndrome, and basement membrane disease (Kopadze et. al., 2021; Papazachariou et. al., 2017). It has also been observed to segregate with disease in related individuals. This variant is almost always reported in cis with the COL4A4 variant c.2320G>C, p.(Gly774Arg) in individuals and families with both dominant and recessive forms of Alport syndrome (Goka et. al., 2021; Papazachariou et. al., 2017). The p.Gly1465Asp variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.007% in gnomAD exomes database. This variant has been reported to the ClinVar database as Pathogenic / Likely pathogenic / Uncertain Significance. The amino acid change p.Gly1465Asp in COL4A4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 1465 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies will be required to confirm the pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001868162	SCV004226007	uncertain significance	not provided	2021-07-27	criteria provided, single submitter	clinical testing	BP2, PP3, PM2_supporting
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000673767	SCV005051729	likely pathogenic	Autosomal recessive Alport syndrome	2024-02-01	criteria provided, single submitter	curation
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001328187	SCV005398835	uncertain significance	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 VUS-3A. Following criteria are met: 0103 - Loss of function is a known mechanism of disease for this gene and is associated with COL4A4-related nephropathy. Dominant negative is a suspected mechanism of disease for this gene as it is a structural protein (PMID: 12028435, 24046192). (I) 0108 - This gene is associated with both recessive and dominant disease. Alport syndrome typically has biallelic inheritance, although rare cases of monoallelic inheritance have been reported. TBMN and focal segmental glomerulosclerosis (FSGS) are associated with autosomal dominant inheritance (OMIM, PMID: 28704582, 16467446, 17942953). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 19 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated collagen IV NC1 domain (PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been classified as likely pathogenic and a VUS by diagnostic laboratories in ClinVar, likely because it has been reported to be in cis with a known pathogenic variant (p.(Gly774Arg)). However, a single family has been reported with Alports disease, where no other variant was detected (ClinVar; PMID: 28632965, 26934356, 24033287). (I) 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
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796256	SCV005418113	uncertain significance	Autosomal recessive Alport syndrome; Hematuria, benign familial, 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4_Supporting+PP3+PP4
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328187	SCV001449267	uncertain significance	Alport syndrome	2018-01-09	no assertion criteria provided	clinical testing	This individual is also homozygous for the c.4394G>A p.(Gly1465Asp) variant in the COL4A4 gene. To our knowledge, this variant has not been previously reported in the literature or any disease specific databases. The c.4394G>A variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.006% (19 out of 275976 alleles). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster all suggest that this variant is likely to be pathogenic. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines.