2-227311838-C-T

Variant names:

• chr2-227311838-C-T
• rs201697532
• NM_000091.5:c.4981C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 7P and 4B. PM1 PM5 PP3_Moderate PP5 BS2

The NM_000091.5(COL4A3):​c.4981C>T​(p.Arg1661Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00059 in 1,613,914 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1661P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (3 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:27 U:1
• Conservation: PhyloP100: 4.62
• Publications: 23 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000091.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-227311839-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2417048.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 2-227311838-C-T is Pathogenic according to our data. Variant chr2-227311838-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287915.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000091.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	NM_000091.5	MANE Select	c.4981C>T	p.Arg1661Cys	missense	Exon 52 of 52	NP_000082.2
	MFF-DT	NR_102371.1		n.48-6183G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.4981C>T	p.Arg1661Cys	missense	Exon 52 of 52	ENSP00000379823.3
	COL4A3	ENST00000469504.2	TSL:1	n.*306C>T		non_coding_transcript_exon	Exon 6 of 6	ENSP00000493493.1
	COL4A3	ENST00000469504.2	TSL:1	n.*306C>T		3_prime_UTR	Exon 6 of 6	ENSP00000493493.1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000357 AC: 89 AN: 249438 AF XY: 0.000332

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000583

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000612 AC: 894 AN: 1461636 Hom.: 3 Cov.: 31 AF XY: 0.000582 AC XY: 423 AN XY: 727104

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.000447 AC: 20 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86210

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000736 AC: 818 AN: 1111888

Other (OTH) AF: 0.000762 AC: 46 AN: 60386

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74446

African (AFR) AF: 0.000144 AC: 6 AN: 41556

American (AMR) AF: 0.000523 AC: 8 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000617 AC: 42 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000571 Hom.: 0

Bravo AF: 0.000419

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000275 AC: 1

ESP6500EA AF: 0.000614 AC: 5

ExAC AF: 0.000306 AC: 37

EpiCase AF: 0.000327

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:27 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:10

Nov 25, 2014

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Jun 16, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 30406062, 36117978, 37734845, 30487145, 30773290, 25229338, 20847057, 33774617, 32939031, 36013122, 32359821, 11134255, 34746741, 34313030, 30586318, 33532864, 37163122, 27485810, Bailo[CaseReport]2021, 26809805, 24052634, 29946535, 38523675, 39071776)

Dec 07, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2_supporting, PM3_very_strong

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1661 of the COL4A3 protein (p.Arg1661Cys). This variant is present in population databases (rs201697532, gnomAD 0.06%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with Alport syndrome (PMID: 11134255, 24052634, 26809805; internal data). 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: 287915). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL4A3 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Jun 01, 2016

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 26, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL4A3: PM3:Very Strong, PM5, PM2:Supporting

Aug 30, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive Alport syndrome Pathogenic:6

Apr 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL4A3 c.4981C>T (p.Arg1661Cys) results in a non-conservative amino acid change located in the collagen IV carboxyl-terminal non-collagenous (NC1) domain (IPR001442) of the encoded protein sequence. 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 0.00036 in 249438 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (0.00036 vs 0.0014). c.4981C>T has been reported in the literature in multiple individuals affected with Alport Syndrome, Autosomal Recessive (e.g., Heidet_2001, Storey_2013, Weber_2016, Connaughton_2019, Savige_2016, Garca-Aznar_2022, Chen_2024, Internal data). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11134255, 24052634, 26809805, 30773290, 27485810, 36013122, 39071776). ClinVar contains an entry for this variant (Variation ID: 287915). Based on the evidence outlined above, the variant was classified as pathogenic.

Feb 01, 2020

Molecular Biology Laboratory, Fundació Puigvert

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Jun 26, 2020

New York Genome Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 17, 2020

Institute of Human Genetics Munich, TUM University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 11, 2016

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This heterozygous missense variant in the COL4A3 gene (autosomal recessive transmission) is present in a male patient with Alport syndrome who also harbours a non-sense variant in the same gene (see below). The segregation analysis could not be done, but regarding the clinical presentation of the patient, it is assumed that these two variants are present in compound heterozygosity

Alport syndrome Pathogenic:4

Sep 05, 2024

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4981C>T;p.(Arg1661Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 287915; PMID: 26809805; PMID: 25229338); PMID: 25229338; PMID: 24052634; PMID: 24052634 - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (C4) - PM1. The p.(Arg1661Cys) was detected in trans with a pathogenic variant (PMID: 26809805; PMID: 24052634; PMID: 24052634) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 26809805; 25229338) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3.and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic.

Jul 24, 2024

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This individual is also heterozygous for the c.4981C>T variant in the COL4A3 gene, which results in the amino acid substitution of arginine to cysteine at residue 1661, p.(Arg1661Cys). This variant has been reported in the gnomAD v4.1.1 browser (http://gnomad.broadinstitute.org accessed: 24/07/2024) with aN allele frequency of 0.05% (953 out of 1613914 alleles, including 3 homozygous individuals). The allele frequency of this variant is too high for this variant to cause fully penetrant autosomal dominant COL4A3 related disorders. However, it has been widely reported in multiple unrelated individuals with autosomal recessive COL4A3 related disorders. In such cases, the c.4981C>T p.(Arg1661Cys) was found in compound heterozygosity with another COL4A3 disease causing variant (Braunisch et al 2018 PMID: 29946535; Weber et al 2016 PMID: 26809805; Storey et al 2013 PMID: 24052634). This variant alters a highly conserved arginine in the NCI domain of COL4A3 (LeBleu et al 2010 PMID: 20847057). In silico analysis of pathogenicity (through Alamut Visual v2.13) using PolyPhen2, SIFT and MutationTaster all suggest that this variant is likely to be pathogenic. This variant is considered to be pathogenic according to the ACMG guidelines (Evidence used: PM3_Very strong, PM1, PM2_Supporting, PP3_Moderate). .

Mar 13, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 for a recessive condition (v2: 99 heterozygotes, 1 homozygote); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic/pathogenic by multiple clinical laboratories in ClinVar. It has also been classified as a VUS in ClinVar. This variant has been reported in several compound heterozygous individuals with Alport syndrome (PMIDs: 24052634, 29946535, 37362409); Missense variant consistently predicted to be damaging by in silico tool or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from arginine to cysteine; This variant is heterozygous; This gene is associated with both recessive and dominant disease; An alternative amino acid change at the same position has been observed in gnomAD (v2) (9 heterozygotes, 0 homozygotes); Variant is located in the annotated C4 domain (DECIPHER); 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); Inheritance information for this variant is not currently available in this individual.

Autosomal dominant Alport syndrome Pathogenic:2

Jul 25, 2019

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 25, 2023

Institute of Human Genetics Munich, TUM University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Alport syndrome 3b, autosomal recessive Pathogenic:1

May 13, 2024

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as likely pathogenic for Alport syndrome spectrum, autosomal recessive. The following ACMG Tag(s) were applied: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3_moderate; REVEL score 0.918). For recessive disorders, detected in trans with a pathogenic variant (PM3_strong; PMID: 24052634, 37362409, 38214412).

COL4A3-related disorder Pathogenic:1

Dec 19, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COL4A3 c.4981C>T variant is predicted to result in the amino acid substitution p.Arg1661Cys. The p.Arg1661 residue lies in the non-collagenous domain. This variant has been reported to be pathogenic for autosomal recessive Alport syndrome when in the presence with another pathogenic variant (Heidet et al. 2001. PubMed ID: 11134255; Storey et al. 2013. PubMed ID: 24052634). This variant in the heterozygous status was also reported in one family with focal segmental glomerulosclerosis (FSGS) (Malone et al. 2014. PubMed ID: 25229338). This variant in the compound heterozygous condition along with another COL4A3 missense variant has been reported in a patient with autosomal recessive focal segmental glomerulosclerosis (FSGS) (Braunisch et al. 2018. PubMed ID: 29946535). This variant is reported in 0.058% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-228176554-C-T). This variant is interpreted as pathogenic.

Hematuria, benign familial, 2;C5882663:Autosomal dominant Alport syndrome;C5882699:Alport syndrome 3b, autosomal recessive Pathogenic:1

Jun 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal dominant Alport syndrome;C5882699:Alport syndrome 3b, autosomal recessive Pathogenic:1

Sep 18, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Benign familial hematuria;C4746745:Autosomal recessive Alport syndrome;C5882663:Autosomal dominant Alport syndrome Pathogenic:1

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Benign familial hematuria Uncertain:1

Jan 01, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.12	D
PhyloP100		4.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MVP		0.98
MPC		0.26
ClinPred		0.27	T
GERP RS		6.1
Varity_R		0.94
gMVP		0.97
Mutation Taster		=29/71	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs201697532; hg19: chr2-228176554;