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

gnomAD frequency: 0.00004  dbSNP: rs533297350

Total submissions: 8

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
Invitae	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	2021-08-10	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 Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000673767	SCV004048009	likely pathogenic	Autosomal recessive Alport syndrome		criteria provided, single submitter	clinical testing	The missense c.4394G>A (p.Gly1465Asp) variant in COL4A4 gene has been reported in individual(s) with clinical features of autosomal dominant Alport syndrome and autosomal recessive Alport syndrome (Fallerini, C et al.,2014; Papazachariou, L et al..2017). It has also been observed to segregate with disease in related individuals. This variant is reported with the allele frequency 0.006% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Likely Pathogenic/Uncertain Significance. 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. The amino acid change p.Gly1465Asp in COL4A4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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
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.