rs868002181

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000091.5(COL4A3):c.2452G>A(p.Gly818Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000735 in 1,414,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10U:1

Conservation

PhyloP100: 6.43

Variant links:

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]

COL4A3 links:

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

MFF-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 2-227280970-G-A is Pathogenic according to our data. Variant chr2-227280970-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 447169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227280970-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5 link	c.2452G>A	p.Gly818Arg	missense_variant	Exon 31 of 52	ENST00000396578.8	NP_000082.2	Q01955-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8 link	c.2452G>A	p.Gly818Arg	missense_variant	Exon 31 of 52	1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000114

AC:

AN:

174872

Hom.:

AF XY:

0.0000215

AC XY:

AN XY:

93174

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000277

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000735

AC:

104

AN:

1414456

Hom.:

Cov.:

AF XY:

0.0000758

AC XY:

AN XY:

699032

show subpopulations

Gnomad4 AFR exome

AF:

0.0000311

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000929

Gnomad4 OTH exome

AF:

0.0000341

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Sep 20, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as a single heterozygous variant in several unrelated individuals with features suggestive of Alport syndrome (Gast et al., 2016; Sen et al., 2017; Connaughton et al., 2019; Yao et al., 2019); of note, one individual inherited this variant from an unaffected parent; Reported with a pathogenic variant on the opposite allele (in trans) with a second COL4A3 variant in an individual with features suggestive of Alport syndrome (Storey et al., 2013); Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A3 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (Stenson et al., 2014; Jais et al., 2000); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 28780565, 24077912, 10752524, 24052634, 30773290, 26346198, 30647093) -

Mar 25, 2016

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

May 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 818 of the COL4A3 protein (p.Gly818Arg). 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 clinical features of Alport syndrome (PMID: 24052634, 26346198, 30586318, 30647093, 30773290; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 447169). 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 COL4A3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Sep 27, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alport syndrome

Pathogenic:2

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Alport syndrome, MONDO:0018965, COL4A3-related. Glycine changes that are part of a G-X-Y repeat in the triple helix of a collagen domain are known to have a dominant negative effect (PMID: 12028435). (I) 0108 - This gene is associated with both recessive (Alport syndrome 2 MIM#203780) and dominant disease (Alport syndrome 3 MIM#104200 and benign familial haematuria MIM#141200) (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional Gly-X-Y motif within the collagen triple helical domain (Protein Data Bank). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least five individuals with Alport syndrome, including individuals with both dominant and recessive disease (ClinVar; PMIDs: 24052634, 26346198, 28780565, 30773290). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Nov 04, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in COL4A3 is predicted to replace glycine with arginine at codon 818, p.(Gly818Arg). The glycine residue is highly conserved (100 vertebrates, Multiz Alignments). This is a glycine-altering variant that alters a critical glycine residue in a collagen triple helix repeat (Gly-X-Y) in the alpha-IV collagenous domain. Glycine substitutions within this functional domain have a well-established pathogenic dominant-negative effect (PMID: 20301386). There is a large physicochemical difference between glycine and arginine. The highest population minor allele frequency in the population database gnomAD v4.1 is 0.009% (101/1,155,078 alleles) in the European (non-Finnish) population. This variant has been reported heterozygous in at least five individuals with phenotypes consistent with COL4A3-related disease (including haematuria, chronic kidney disease, and focal segmental glomerulosclerosis), and segregates with disease in multiple families (PMID: 28780565, 26346198, 30647093, 30773290, 38993907). This variant has been detected as compound heterozygous in at least two individuals with Alport syndrome, with at least one pathogenic variant confirmed on the second allele (PMID: 24052634, 30586318). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.987) and predicts no impact on splicing (SpliceAI) for the nucleotide change. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PM1, PM2_Supporting, PM3, PP1_Moderate, PP3_Moderate, PS4_Supporting. -

COL4A3-related disorder

Pathogenic:1

Dec 20, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COL4A3 c.2452G>A variant is predicted to result in the amino acid substitution p.Gly818Arg. This variant was reported in the compound heterozygous state in an individual with Alport syndrome (Patient 11, Storey et al. 2013. PubMed ID: 24052634). This variant was also reported, along with another variant in COL4A3 (phase not noted) in siblings with likely Alport disease and likely hereditary nephritis (Family F2, Gast et al. 2016. PubMed ID: 26346198) and in an individual with glomerulopathy (Supplemental Table 7, Patient ID: CKD152, Groopman et al. 2019. PubMed ID: 30586318). This variant was also reported with a COL4A4 missense variant in an individual with Alport syndrome and both were maternally inherited (Supplemental Table 2, Patient 7, Sen et al. 2017. PubMed ID: 28780565). Of note, for that patient the variant was reported to track with disease in four affected and two unaffected individuals. This variant was also reported in the heterozygous state in an individual with hematuria (Family ID: B2347, Individual ID: 17, Connaughton et al. 2019. PubMed ID: 30773290) and in an individual with steroid-resistant nephrotic syndrome, undescended testes, and a penile anomaly (Supplemental Table 2, Patient 64, Sen et al. 2017. PubMed ID: 28780565). Of note the second patient listed also carried a de novo WT1 variant and the COL4A3 variant was inherited from an unaffected father. This variant was also reported in the heterozygous state in an individual with focal segmental glomerulosclerosis (FSGF) (Patient 7215, Family F23, Yao et al. 2019. PubMed ID: 30647093). This variant is reported in 0.0028% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-228145686-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance, to likely pathogenic, to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/447169/). The p.Gly818Arg residue is located in the conserved triple helical domain, where substitutions of the glycine are usually pathogenic (UniProt residues 43-1438, Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK21582/). Taken together, this variant is interpreted as likely pathogenic. -

Hematuria, benign familial, 2;C5882663:Autosomal dominant Alport syndrome;C5882699:Alport syndrome 3b, autosomal recessive

Pathogenic:1

Feb 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant Alport syndrome

Pathogenic:1

Feb 14, 2019

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Autosomal recessive Alport syndrome

Uncertain:1

Nov 10, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

NM_000091.4(COL4A3):c.2452G>A(G818R) is a missense variant classified as a variant of uncertain significance in the context of COL4A3-related Alport syndrome. G818R has been observed in cases with relevant disease (PMID: 30773290, 28780565, 26346198, 24052634). Functional assessments of this variant are not available in the literature. G818R has been observed in population frequency databases (gnomAD: NFE 0.003%). In summary, there is insufficient evidence to classify NM_000091.4(COL4A3):c.2452G>A(G818R) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.034

Polyphen

1.0

Vest4

0.72

MutPred

0.99

Gain of MoRF binding (P = 0.0118);

MVP

0.90

MPC

0.23

ClinPred

1.0

GERP RS

5.5

Varity_R

0.98

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over