Submissions for variant NM_000091.5(COL4A3):c.3829G>A (p.Gly1277Ser)

gnomAD frequency: 0.00035  dbSNP: rs190598500

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671820	SCV000796842	uncertain significance	Autosomal recessive Alport syndrome	2018-01-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727653	SCV000854957	likely pathogenic	not provided	2018-04-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001143340	SCV001303860	uncertain significance	Alport syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Molecular Biology Laboratory, Fundació Puigvert	RCV001281229	SCV001425004	uncertain significance	Autosomal dominant Alport syndrome	2021-05-31	criteria provided, single submitter	research
GeneDx	RCV000727653	SCV001765592	uncertain significance	not provided	2022-09-15	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in patients in published literature with focal segmental glomerulosclerosis or Alport syndrome (Heidet et al., 2001; Larsen et al., 2016); Identified in patients with childhood IgA-nephropathy, which may present as a phenocopy of Alport syndrome with microhematuria, proteinuria, and end-stage renal disease (Cambier et al., 2021); Identified in a patient in published literature with congenital nephrotic syndrome who also harbored two variants in the NPHS1 gene (Bullich et al., 2015); Proposed to act in a digenic manner with variants in COL4A4 and COL4A5 in multiple families with features of Alport syndrome, resulting in a more severe phenotype; however, disease segregation in these families may be unrelated to the COL4A3 variant (Fallerini et al., 2017); 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: 11134255, 29924831, 33532864, 26795916, 25407002, 27859054, 34013111, 35177655, 32483926, 34400539)
Mendelics	RCV002249398	SCV002518133	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
DASA	RCV001143340	SCV002526416	likely pathogenic	Alport syndrome	2022-06-10	criteria provided, single submitter	clinical testing	The c.3829G>A;p.(Gly1277Ser) missense change has been observed in affected individual(s) (PMID: 27859054; PMID: 25407002; 35177655) - PS4. The variant is present at low allele frequencies population databases (rs190598500– gnomAD 0.003417%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Gly1277Ser) was detected in trans with a Pathogenic variant (PMID: 25407002) - PM3_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 27859054) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002249398	SCV002547818	uncertain significance	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: COL4A3 c.3829G>A (p.Gly1277Ser) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) 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 3 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 allele was found at a frequency of 0.00032 in 1614042 control chromosomes in the gnomAD database, including 2 homozygotes (gnomAD v4). This frequency is not significantly higher than estimated for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (0.00032 vs 0.0014), allowing no conclusion about variant significance. c.3829G>A has been reported in the literature in many heterozygous individuals affected with hematuria, however the variant was found to co-occur with other potentially pathogenic variants, including those in COL4A4 and COL4A5, in several individuals (e.g., Bullich_2015, Fallerini_2017, Lucas_2018, Heidet_2001, Cambier_2021, Domingo-Gallego_2021, Larsen_2016, Furlano_2021, Yavas_2022, Doreille_2023). Additionally, the variant was found in one compound heterozygous child affected with IgA nephropathy (e.g., Cambier_2021) and in one very young homozygous proband affected with bilateral, prelingual deafness and early onset myopia where the variant was shown to segregate with disease in a recessive manner in related individuals (e.g., AitRaise_2022). These data indicate that the variant may be associated with autosomal recessive disease or may contribute to disease severity in individuals with co-occurring pathogenic COL4A4/5 variants. 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: 35301649, 25407002, 34013111, 33532864, 27859054, 33838161, 11134255, 26795916, 29924831, 36134775, 36938085). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (likely pathogenic, n = 4; VUS, n = 8; likely benign, n = 1). Based on the evidence outlined above, in the context of autosomal recessive disease or digenic inheritance with a pathogenic COL4A4 or COL4A5 variant, the variant was classified as VUS-possibly pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV001281229	SCV002764996	likely pathogenic	Autosomal dominant Alport syndrome	2022-03-15	criteria provided, single submitter	clinical testing
Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria	RCV002485556	SCV002769824	uncertain significance	focal and segmental glomerulosclerosis	2022-12-28	criteria provided, single submitter	clinical testing	The c.3829G>A (p.Gly1277Ser) COL4A3 variant in heterocigous state has been reported in our laboratory in a 64-year-old female patient with a clinical diagnosis of nephrotic syndrome, long-term hypertension, dyslipidemia, overweight, and intolerance to steroids and mycophenolate. In a renal biopsy, focal and segmental glomerulosclerosis was observed. Immunological study and renal ultrasound were normal. She is the eldest of 9 siblings and has no relevant family nephrological history. This variant is present in population databases (gnomAD allele frequency 0.0003633). ClinVar contains an entry for this variant (Variation ID: 555905). It has been described in the scientific literature in numerous individuals with various nephrological disorders (Alport AD/AR, IgA nephropathy, nephrotic syndrome, keratoconus, benign hematuria), usually sporadic cases, without segregation between individuals in the same family and with diverse phenotypes, in occasions in co-occurrence with other variants that justified the clinical disease. In silico analysis (CADD, PolyPhen-2, MutationTaster, SIFT and Provean) supports that this missense variant has a deleterious effect on protein structure/function, but this prediction has not been confirmed by functional studies. In summary, the available evidence for c.3829G>A (p.Gly1277Ser) COL4A3 variant is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Invitae	RCV000727653	SCV003293751	likely benign	not provided	2024-01-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000727653	SCV003799943	uncertain significance	not provided	2022-03-29	criteria provided, single submitter	clinical testing	The COL4A3 c.3829G>A; p.Gly1277Ser variant (rs190598500) has been reported in several individuals diagnosed with Alport syndrome, nephropathy, or glomerulosclerosis (Bullich 2015, Domingo-Gallego 2022, Fallerini 2017, Heidet 2001, Larsen 2016, Lucas 2018). However, several of these individuals had variants in other genes that represented an alternative molecular mechanism for disease (Bullich 2015, Domingo-Gallego 2022, Fallerini 2017). The variant is reported as a variant of uncertain significance by several sources in the ClinVar database (Variation ID: 555905) and is reported in the general population with an allele frequency of 0.036% (102/280,750 alleles) in the Genome Aggregation Database. The glycine at codon 1277 occurs in a Gly-X-Y repeat region, but this domain is not predicted to be a collagen triple helix region (UniProt Q01955). The glycine at this position is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.971). However, due to conflicting information, the clinical significance of the p.Gly1277Ser variant is uncertain at this time. References: Bullich G et al. Targeted next-generation sequencing in steroid-resistant nephrotic syndrome: mutations in multiple glomerular genes may influence disease severity. Eur J Hum Genet. 2015 Sep;23(9):1192-9. PMID: 25407002. Domingo-Gallego A et al. Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players. Nephrol Dial Transplant. 2022 Mar 25;37(4):687-696. PMID: 33532864. Fallerini C et al. Alport syndrome: impact of digenic inheritance in patients management. Clin Genet. 2017 Jul;92(1):34-44. PMID 27859054. Heidet L et al. Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome. J Am Soc Nephrol. 2001 Jan;12(1):97-106. PMID 11134255. Larsen CP et al. A Custom Targeted Next-Generation Sequencing Gene Panel for the Diagnosis of Genetic Nephropathies. Am J Kidney Dis. 2016 Jun;67(6):992-3. PMID: 26795916. Lucas SEM et al. Rare, potentially pathogenic variants in 21 keratoconus candidate genes are not enriched in cases in a large Australian cohort of European descent PLoS One. 2018 Jun 20;13(6):e0199178. PMID 29924831.
PreventionGenetics, part of Exact Sciences	RCV003392513	SCV004119910	likely pathogenic	COL4A3-related disorder	2023-01-16	criteria provided, single submitter	clinical testing	The COL4A3 c.3829G>A variant is predicted to result in the amino acid substitution p.Gly1277Ser. This variant has been reported in the heterozygous state in a patient with Alport syndrome (Heidet et al. 2001. PubMed ID: 11134255), and in the heterozygous state in patients with Alport syndrome from three families in which potentially pathogenic variants in COL4A4 and COL4A5 were also identified (Fallerini et al. 2017. PubMed ID: 27859054). This variant has also been reported in patients with steroid-resistant nephrotic syndrome and/or focal segmental glomerulosclerosis, although in some of these patients potentially pathogenic variants in other genes were again also identified (Bullich et al. 2014. PubMed ID: 25407002; Table D, Larsen et al. 2016. PubMed ID: 26795916). The c.3829G>A has been reported in the compound heterozygous, heterozygous or with a COL4A4 variant in additional individuals with COL4A3-related phenotypes (Cambier et al. 2021. PubMed ID: 34013111; Table S2. Domingo-Gallego et al. 2022. PubMed ID: 33532864). Using the Genomics England 100,000 Genomes Project database, one study found 2 individuals heterozygous for c.3829G>A with hematuria, while there were 28 heterozygous individuals without hematuria reported in clinical records (Supp. Table 4 in Gibson J et al 2021. PubMed ID: 34400539). This variant resides in the collagen triple helix repeat, where glycine substitutions are expected to be pathogenic (Savige et al. 2021. PubMed ID: 33854215). This variant is reported in 0.090% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-228163475-G-A). While this variant does not appear to be a highly penetrant, dominant variant, it is observed in a significant number of patients with nephrological disorders and occurs at a Gly residue. This variant is interpreted as likely pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003992367	SCV004810059	uncertain significance	Alport syndrome 3b, autosomal recessive	2024-04-04	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000727653	SCV001554089	uncertain significance	not provided		no assertion criteria provided	clinical testing	The COL4A3 p.Gly1277Ser variant was identified in 6 of 388 proband chromosomes (frequency: 0.0155) from individuals or families with Alport syndrome and steroid-resistant nephrotic syndrome/focal segmental glomerulosclerosis (Fallerini_2017_PMID:27859054, Bullich_2015_PMID:25407002, Gillion_2018_PMID:29854973, Heidet_2001_PMID:11134255). The variant was also identified in dbSNP (ID: rs190598500), ClinVar (classified as conflicting interpretations of pathogenicity with uncertain significance reported by Counsyl and likely pathogenic reported by EGL Genetic Diagnostics; associated condition is Alport syndrome), and LOVD 3.0; it was not identified in the Cosmic database. The variant was identified in control databases in 102 of 280750 chromosomes at a frequency of 0.000363 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 32 of 35360 chromosomes (freq: 0.000905), Other in 6 of 7144 chromosomes (freq: 0.00084), European (non-Finnish) in 63 of 128552 chromosomes (freq: 0.00049) and African in 1 of 24178 chromosomes (freq: 0.000041), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) or South Asian populations. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Gly1277 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000727653	SCV001954784	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000727653	SCV001970679	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001143340	SCV002076426	uncertain significance	Alport syndrome	2020-04-03	no assertion criteria provided	clinical testing