rs201697532

chr2-227311838-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM5 PP3_Moderate PP5

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. R1661H) has been classified as 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:21 U:2
• Conservation: PhyloP100: 4.62

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_pathogenic. Variant got 7 ACMG points.

• PM1: In a strand (size 5) in uniprot entity CO4A3_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000091.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-227311839-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1500473.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 id is 287915.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=7, Likely_pathogenic=13}. Variant chr2-227311838-C-T is described in Lovd as [Pathogenic]. Variant chr2-227311838-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A3	NM_000091.5	c.4981C>T	p.Arg1661Cys	missense_variant	52/52	ENST00000396578.8
MFF-DT	NR_102371.1	n.48-6183G>A		intron_variant, non_coding_transcript_variant
COL4A3	XM_005246277.4	c.4876C>T	p.Arg1626Cys	missense_variant	51/51

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8	c.4981C>T	p.Arg1661Cys	missense_variant	52/52	1	NM_000091.5	P1
MFF-DT	ENST00000439598.6	n.48-6183G>A		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.000357 AC: 89 AN: 249438 Hom.: 1 AF XY: 0.000332 AC XY: 45 AN XY: 135340

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000736

Gnomad4 OTH exome AF: 0.000762

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

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000567 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:21 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	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; 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: 287915). 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 95%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2023	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, 30487145, 30773290, 25229338, 20847057, 33774617, 32939031, 36013122, 32359821, 11134255, 34746741, 34313030, 30586318, 33532864, 37163122, 27485810, Bailo[CaseReport]2021, 26809805, 24052634, 29946535) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 25, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 07, 2022	PP3, PM2_supporting, PM3_very_strong -

Autosomal recessive Alport syndrome Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 17, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 16, 2021	Variant summary: COL4A3 c.4981C>T (p.Arg1661Cys) results in a non-conservative amino acid change in 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 higher than expected for a pathogenic variant in COL4A3 causing Autosomal Recessive Alport Syndrome (0.0019), allowing no conclusion about variant significance. The c.4981C>T has been reported in the literature in at least three individuals affected with Autosomal Recessive Alport Syndrome with other (likely) pathogenic COL4A3 variants in trans (Storey_2013, ClinVar: SCV000537703.1). In addition, the variant was also reported in several individuals affected with Alport syndrome where the other variant in trans was not specified (e.g. Heidet_2001, Weber_2016, Savige_2016). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=2) / likely pathogenic (n=6) or VUS (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Jul 11, 2016	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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 26, 2020	- -

Autosomal dominant Alport syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 10, 2019	A heterozygous missense variant, NM_000091.4(COL4A3):c.4981C>T, has been identified in exon 52 of 52 of the COL4A3 gene. The variant is predicted to result in a major amino acid change from arginine to cysteine at position 1661 of the protein (NP_000082.2(COL4A3):p.(Arg1661Cys)). The arginine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the C4 functional domain. In silico predictions for this variant are consistently pathogenic (PolyPhen, SIFT, CADD, MutationTaster). The variant is present in the gnomAD database at a frequency of 0.036% (99 heterozygotes; 1 homozygote). An alternative residue change to histidine has been reported in the gnomAD database at a frequency of 0.0032%. The variant has previously been described as pathogenic in multiple patients with Alport syndrome and segregated with disease in both heterozygous and compound heterozygous states, however it has also recently been reported as a Variant of Uncertain Significance (ClinVar, Heidet, L. et al. (2001), Storey, H. et al. (2013), Malone, A. et al. (2014), Braunisch, MC. et al. (2018)). Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. -
Likely pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Jul 25, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 25, 2023	- -

Alport syndrome Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Oct 12, 2017	This individual is also heterozygous for the c.4981C>T p.(Arg1661Cys) variant in the COL4A3 gene. This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with an allele frequency of 0.059% (76/126650 alleles including one homozygote). It has also been previously described in the literature in patients with Alport syndrome with both autosomal dominant and recessive inheritance (Heidet et al 2001 J Am Soc Nephrol 12:97, Storey et al 2013 J Am Soc Nephrol 24:1945, Malone et al 2014 Kidney Int 86:1253). This variant is reported in ClinVar as likely pathogenic in two individuals, however no details were provided. In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster suggest that this variant is likely to be pathogenic. As Alport syndrome due to COL4A3 variants can be autosomal dominant or recessive it is not clear if this variant is disease causing. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	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. -

COL4A3-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2022

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. -

Benign familial hematuria;C4746547:Autosomal dominant Alport syndrome;C4746745:Autosomal recessive Alport syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 30, 2021

- -

Alport syndrome 3b, autosomal recessive Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

May 13, 2024

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). -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D
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

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: rs201697532; hg19: chr2-228176554;