rs190598500

Positions:

• chr2-227298759-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP3_Moderate PP5 BS2

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:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:13 B:1
• Conservation: PhyloP100: 7.74

Genes affected

COL4A3 (HGNC:2204): (collagen type IV alpha 3 chain) Type IV collagen, the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen. This gene encodes alpha 3. In the Goodpasture syndrome, autoantibodies bind to the collagen molecules in the basement membranes of alveoli and glomeruli. The epitopes that elicit these autoantibodies are localized largely to the non-collagenous C-terminal domain of the protein. A specific kinase phosphorylates amino acids in this same C-terminal region and the expression of this kinase is upregulated during pathogenesis. This gene is also linked to an autosomal recessive form of Alport syndrome. The mutations contributing to this syndrome are also located within the exons that encode this C-terminal region. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jun 2010]

MFF-DT (HGNC:41067): (MFF divergent transcript)

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849
• PP5: Variant 2-227298759-G-A is Pathogenic according to our data. Variant chr2-227298759-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555905.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=9, Likely_benign=1, Pathogenic=1}. Variant chr2-227298759-G-A is described in Lovd as [Pathogenic]. Variant chr2-227298759-G-A is described in Lovd as [Likely_pathogenic].
• BS2: High Homozygotes in GnomAdExome4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A3	NM_000091.5	c.3829G>A	p.Gly1277Ser	missense_variant	43/52	ENST00000396578.8
MFF-DT	NR_102371.1	n.243+6701C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8	c.3829G>A	p.Gly1277Ser	missense_variant	43/52	1	NM_000091.5	P1
MFF-DT	ENST00000439598.6	n.243+6701C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000377 AC: 94 AN: 249374 Hom.: 0 AF XY: 0.000340 AC XY: 46 AN XY: 135330

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000513

Gnomad OTH exome AF: 0.000990

GnomAD4 exome AF: 0.000323 AC: 472 AN: 1461760 Hom.: 2 Cov.: 31 AF XY: 0.000319 AC XY: 232 AN XY: 727166

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000962

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000328

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74472

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000293 Hom.: 0

Bravo AF: 0.000385

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000243 AC: 2

ExAC AF: 0.000339 AC: 41

EpiCase AF: 0.000382

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:13 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:5 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 25, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2022	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) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 29, 2022	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. -

Autosomal dominant Alport syndrome Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	May 01, 2024	Pathogenic by Deafness Variation Database and by 4 ClinVar submissions. -
Uncertain significance, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	May 31, 2021	- -

Alport syndrome Pathogenic:1 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	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 -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 03, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 15, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

COL4A3-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2023

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. -

Alport syndrome 3b, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Apr 04, 2024

- -

focal and segmental glomerulosclerosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria

Dec 28, 2022

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. -

Autosomal recessive Alport syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jan 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.96
MPC		0.19
ClinPred		0.23	T
GERP RS		5.4
Varity_R		0.82
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs190598500; hg19: chr2-228163475;