Submissions for variant NM_000092.5(COL4A4):c.1223G>A (p.Gly408Glu)

gnomAD frequency: 0.00002  dbSNP: rs1026613471

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000681805	SCV001143228	likely pathogenic	not provided	2019-05-02	criteria provided, single submitter	clinical testing	The variant disrupts a glycine residue in the canonical Gly-X-Y repeats of the triple helix domain, which are required for stability and structure of this protein. Therefore it is expected to severely affect the function of the protein. The best available variant frequency is uninformative because it is below the disease allele frequency.
Invitae	RCV000681805	SCV001219500	pathogenic	not provided	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 408 of the COL4A4 protein (p.Gly408Glu). This variant is present in population databases (no rsID available, gnomAD 0.05%). This missense change has been observed in individuals with clinical features of Alport syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 562349). 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.
Fulgent Genetics, Fulgent Genetics	RCV002499205	SCV002808741	pathogenic	Autosomal recessive Alport syndrome; Benign familial hematuria	2022-04-05	criteria provided, single submitter	clinical testing
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV002512123	SCV002822967	likely pathogenic	Autosomal recessive Alport syndrome	2019-11-11	criteria provided, single submitter	clinical testing	The c.1223G>A variant in the COL4A4 gene is a missense variant, which results in the substitution of the highly conserved glycine residue at the 408 position to glutamic acid (p.Gly408Glu). This variant localizes to coding exon 20 of the COL4A4 gene (48 exons total; NP_000083.3) and is within the triple helical domain of the protein. To the best of our knowledge, this specific variant has not been described to be associated with disease. However, glycine substitutions within the triple helical domain of this protein are a known mechanism of disease. In silico analysis predicts this change to be deleterious and damaging to the structure and/or function of the protein (probably damaging by PolyPhen2 and damaging by SIFT). This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (6/248,574), indicating it is not a common benign variant in the populations represented in this database. Of note, allele frequency is higher among individuals of Ashkenazi Jewish descent (5/10,026). Based on the evidence presented, this variant is classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004535702	SCV004116833	likely pathogenic	COL4A4-related disorder	2023-04-05	criteria provided, single submitter	clinical testing	The COL4A4 c.1223G>A variant is predicted to result in the amino acid substitution p.Gly408Glu. This variant was reported in the heterozygous state in an individual with glomerulopathy and family history of kidney disease (Table S7. Groopman et al 2019. PubMed ID: 30586318). At PreventionGenetics, we have observed the c.1223G>A variant in the heterozygous state in a patient with microhematuria and proteinuria and in another patient with Alport syndrome who also carried a COL4A4 nonsense variant (internal data). The Gly408Glu variant affects a Gly residue of the conserved triple helical domain (residues 65 – 1459) of the COL4A4 protein (uniprot.org). The majority of pathogenic variants in COL4A4 substitute a glycine residue to a bulkier amino acid in the triple-helical domain (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). This variant is reported in 0.050% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-227958987-C-T). This variant is interpreted as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002512123	SCV005040479	likely pathogenic	Autosomal recessive Alport syndrome	2024-03-01	criteria provided, single submitter	clinical testing	Variant summary: COL4A4 c.1223G>A (p.Gly408Glu) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. 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 2.4e-05 in 248574 control chromosomes. c.1223G>A has been reported in the literature in individuals affected with Hematuria, Benign Familial. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 562349). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Gharavi Laboratory, Columbia University	RCV000681805	SCV000809275	likely pathogenic	not provided	2018-09-16	no assertion criteria provided	research