Submissions for variant NM_000091.5(COL4A3):c.4981C>T (p.Arg1661Cys)

gnomAD frequency: 0.00039  dbSNP: rs201697532

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000516971	SCV000341862	likely pathogenic	not provided	2016-06-01	criteria provided, single submitter	clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000283598	SCV000537703	likely pathogenic	Autosomal recessive Alport syndrome	2016-07-11	criteria provided, single submitter	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
Athena Diagnostics Inc	RCV000516971	SCV000612952	pathogenic	not provided	2014-11-25	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000677316	SCV000803483	uncertain significance	Autosomal dominant Alport syndrome	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Alport syndrome, autosomal recessive, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:24052634). BS2-Supporting => BS2 downgraded in strength to supporting.
Gharavi Laboratory, Columbia University	RCV000516971	SCV000809140	pathogenic	not provided	2018-09-16	criteria provided, single submitter	research
Invitae	RCV000516971	SCV000947691	pathogenic	not provided	2024-01-22	criteria provided, single submitter	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; 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.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000283598	SCV001149721	likely pathogenic	Autosomal recessive Alport syndrome	2020-01-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001141624	SCV001301983	uncertain significance	Alport syndrome	2017-04-27	criteria provided, single submitter	clinical testing	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.
Molecular Biology Laboratory, Fundació Puigvert	RCV000283598	SCV001425009	likely pathogenic	Autosomal recessive Alport syndrome	2020-02-01	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000677316	SCV001427178	likely pathogenic	Autosomal dominant Alport syndrome	2019-02-10	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000283598	SCV001623176	likely pathogenic	Autosomal recessive Alport syndrome	2021-04-16	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV001536080	SCV001752781	likely pathogenic	Autosomal dominant Alport syndrome; Autosomal recessive Alport syndrome; Benign familial hematuria	2021-06-30	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000283598	SCV001810359	likely pathogenic	Autosomal recessive Alport syndrome	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000516971	SCV002023300	likely pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000283598	SCV002025639	likely pathogenic	Autosomal recessive Alport syndrome	2020-06-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000516971	SCV002072821	pathogenic	not provided	2023-09-15	criteria provided, single submitter	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, 30487145, 30773290, 25229338, 20847057, 33774617, 32939031, 36013122, 32359821, 11134255, 34746741, 34313030, 30586318, 33532864, 37163122, 27485810, Bailo[CaseReport]2021, 26809805, 24052634, 29946535)
DASA	RCV001141624	SCV002107094	pathogenic	Alport syndrome	2022-03-05	criteria provided, single submitter	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.
AiLife Diagnostics, AiLife Diagnostics	RCV000516971	SCV002503206	likely pathogenic	not provided	2021-03-26	criteria provided, single submitter	clinical testing
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000677316	SCV004045912	likely pathogenic	Autosomal dominant Alport syndrome	2023-01-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003401260	SCV004110540	pathogenic	COL4A3-related condition	2022-12-19	criteria provided, single submitter	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000516971	SCV004225726	pathogenic	not provided	2022-12-07	criteria provided, single submitter	clinical testing	PP3, PM2_supporting, PM3_very_strong
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000677316	SCV001192760	likely pathogenic	Autosomal dominant Alport syndrome	2019-07-25	no assertion criteria provided	clinical testing
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001141624	SCV001449247	uncertain significance	Alport syndrome	2017-10-12	no assertion criteria provided	clinical testing	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.