rs190598500
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_000091.5(COL4A3):c.3829G>A(p.Gly1277Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000325 in 1,614,042 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1277G) has been classified as Likely benign.
Frequency
Consequence
NM_000091.5 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| COL4A3 | NM_000091.5 | c.3829G>A | p.Gly1277Ser | missense_variant | Exon 43 of 52 | ENST00000396578.8 | NP_000082.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| COL4A3 | ENST00000396578.8 | c.3829G>A | p.Gly1277Ser | missense_variant | Exon 43 of 52 | 1 | NM_000091.5 | ENSP00000379823.3 |
Frequencies
GnomAD3 genomes 0.000342 AC: 52AN: 152162Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000377 AC: 94AN: 249374 AF XY: 0.000340 show subpopulations
GnomAD4 exome AF: 0.000323 AC: 472AN: 1461760Hom.: 2 Cov.: 31 AF XY: 0.000319 AC XY: 232AN XY: 727166 show subpopulations
Age Distribution
GnomAD4 genome 0.000341 AC: 52AN: 152282Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22AN XY: 74472 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:5Benign:1
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. -
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Identified in the heterozygous state in patients in published literature with focal segmental glomerulosclerosis or Alport syndrome (PMID: 11134255, 26795916); Identified in patients with childhood IgA-nephropathy, which may present as a phenocopy of Alport syndrome with microhematuria, proteinuria, and end-stage renal disease (PMID: 34013111); Identified in a patient in published literature with congenital nephrotic syndrome who also harbored two variants in the NPHS1 gene (PMID: 25407002); Observed in homozygous state in a patient with bilateral prelingual sensorineural hearing loss in the literature (PMID: 35301649); 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 (PMID: 27859054); 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: 29924831, 26795916, 35177655, 32483926, 34400539, 36617405, 25407002, 34013111, 11134255, 33532864, 36938085, 33838161, 36134775, 30476936, 35301649, 27859054, 38357258) -
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. -
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Autosomal dominant Alport syndrome Pathogenic:2Uncertain:1Benign:1
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Pathogenic by Deafness Variation Database and by 4 ClinVar submissions. -
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GnomAD exomes allele frequency = 0.000323 is greater than 0.000316 (threshold derived from the 2 184 clinically reported variants in gene COL4A3), good gnomAD exomes coverage = 31.5 (BS1). Observed in healthy adults: gnomAD exomes homozygous allele count = 2 is greater or equal to 2 for AD/AR gene COL4A3, good gnomAD exomes coverage = 31.5 (BS2). Combined evidence strength is Moderate (score = 2).Moderate: ClinVar classifies this variant as Uncertain Significance but a high confidence submitter has classified as Likely Benign (BP6). UniProt protein CO4A3_HUMAN region of interest 'Disordered' has 471 missense/in-frame variants (184 pathogenic variants, 263 uncertain variants and 24 benign variants), which qualifies as moderate pathogenic.UniProt protein CO4A3_HUMAN region of interest 'Triple-helical region' has 720 missense/in-frame variants (270 pathogenic variants, 408 uncertain variants and 42 benign variants), which qualifies as moderate pathogenic (PM1). Combined evidence strength is Moderate (score = 2).Supporting: a VarSome user has classified this variant as Pathogenic (automatically lifted-over from chr2:228163475 G⇒A on hg19) (PP5). etaRNN = 0.849 is between 0.841 and 0.939 ⇒ moderate pathogenic. Reducing to strength Supporting in view of the clinical evidence reported in BP6_Moderate (PP3). We identified this variant in a 24-year-old female patient with Alport syndrome 3A, autosomal dominant. -
Alport syndrome Pathogenic:1Uncertain:2
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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. -
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 -
not specified Uncertain:1Benign:1
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Variant summary: COL4A3 c.3829G>A (p.Gly1277Ser) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00032 in 1614042 control chromosomes, predominantly at a frequency of 0.001 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (0.00032 vs 0.0014). However, in the Middle Eastern subpopulation, the gnomAD frequency slightly exceeds (0.001825) the maximum pathogenic allele frequency expected for recessive Alport syndrome. Further, 2 homozygous controls have also been reported in the gnomAD database, which may be inconsistent with the severity and penetrance expected for recessive COL4A3-related conditions. 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). 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, 36938085, 27859054, 33838161, 11134255, 26795916, 29924831, 36134775, 34400539, 38357258, 28657137, 35177655, 38471460, 38972501, 36617405, 34400539, 35675912, 38868576, 30476936, 32483926, 35759000, 26359337, 39190485, 39408606). ClinVar contains an entry for this variant (Variation ID: 555905). Based on the evidence outlined above, the variant was classified as likely benign. -
COL4A3-related disorder Pathogenic:1
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; Table 2 in Yavaş et al. 2022. PubMed ID: 36134775). 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. 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. -
Alport syndrome 3b, autosomal recessive Uncertain:1
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focal and segmental glomerulosclerosis Uncertain:1
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. -
Hematuria, benign familial, 2;C5882663:Autosomal dominant Alport syndrome;C5882699:Alport syndrome 3b, autosomal recessive Uncertain:1
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Autosomal recessive Alport syndrome Uncertain:1
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at