Submissions for variant NM_000091.5(COL4A3):c.361G>A (p.Gly121Ser)

gnomAD frequency: 0.00001  dbSNP: rs778886174

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825317	SCV000966612	uncertain significance	not specified	2018-08-08	criteria provided, single submitter	clinical testing	The p.Gly121Ser variant in COL4A3 has not been previously reported in individual s with hearing loss or Alport syndrome but has been identified in 4/33538 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org; dbSNP rs778886174). Although this variant has been seen in the genera l population, its frequency is not high enough to rule out a pathogenic role. Th is variant has also been reported in ClinVar (Variation ID 522453). Computationa l prediction tools and conservation analysis suggest that the p.Gly121Ser varian t may impact the protein, though this information is not predictive enough to de termine pathogenicity. In summary, the clinical significance of the p.Gly121Ser variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_Supporting.
Medical Genetics, University of Parma	RCV001089905	SCV001245138	likely pathogenic	Autosomal recessive Alport syndrome	2020-03-11	criteria provided, single submitter	clinical testing
University of Iowa Renal Genetics Clinic, University of Iowa	RCV001169840	SCV001250653	likely pathogenic	Autosomal dominant Alport syndrome; Autosomal recessive Alport syndrome; Benign familial hematuria	2019-07-17	criteria provided, single submitter	clinical testing	The Gly121Ser variant in COL4A3 has been identified within a 62-year-old female with a history of hematuria, proteinuria, end-stage kidney disease, and IgA nephropathy on kidney biopsy. This individual's 41-year-old daughter has a history of microscopic hematuria and was found to have the Gly121Ser variant as well. This variant meets the following 2015 ACMG Guideline criteria: PM1, PM2, PP2, and PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001855319	SCV002158333	uncertain significance	not provided	2024-01-04	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 121 of the COL4A3 protein (p.Gly121Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Alport syndrome (PMID: 33369211). ClinVar contains an entry for this variant (Variation ID: 522453). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001855319	SCV004564188	likely pathogenic	not provided	2023-05-03	criteria provided, single submitter	clinical testing	The COL4A3 c.361G>A; p.Gly121Ser variant (rs778886174) is reported in the literature in two compound heterozygous individuals with autosomal recessive Alport syndrome (Uliana 2021). This variant is also reported in ClinVar (Variation ID: 522453) and is found in the general population with an overall allele frequency of 0.003% (8/280812 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.908). Additionally, this glycine occurs in a Gly-X-Y repeat region in a collagen triple helix region, a critical functional domain (Savige 2021). Based on the available information, this variant is considered to be likely pathogenic. References: Savige J et al. Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria. Eur J Hum Genet. 2021 Aug;29(8):1186-1197. PMID: 33854215. Uliana V et al. Deciphering the pathogenesis of the COL4-related hematuric nephritis: A genotype/phenotype study. Mol Genet Genomic Med. 2021 Feb;9(2):e1576. PMID: 33369211.
Ambry Genetics	RCV004025283	SCV004929677	uncertain significance	Inborn genetic diseases	2023-09-15	criteria provided, single submitter	clinical testing	The c.361G>A (p.G121S) alteration is located in exon 6 (coding exon 6) of the COL4A3 gene. This alteration results from a G to A substitution at nucleotide position 361, causing the glycine (G) at amino acid position 121 to be replaced by a serine (S). Based on data from gnomAD, the A allele has an overall frequency of 0.003% (8/280812) total alleles studied. The highest observed frequency was 0.014% (5/35334) of Latino alleles. This amino acid position is highly conserved in available vertebrate species. The p.G212 amino acid is located within the triple-helical domain of the collagen type IV alpha 3 chain and this variant affects one of the highly conserved glycine residues in the Gly-X-Y motif that make up this domain (Ramshaw, 1998). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV001855319	SCV005332347	uncertain significance	not provided	2024-03-14	criteria provided, single submitter	clinical testing	Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A3 gene; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34632641, 33369211)
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000625594	SCV000746093	likely pathogenic	Autosomal dominant Alport syndrome	2017-09-18	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001834978	SCV002076378	uncertain significance	Alport syndrome	2020-08-17	no assertion criteria provided	clinical testing