ClinVar Miner

Submissions for variant NM_000092.5(COL4A4):c.81_86del (p.27IL[1])

dbSNP: rs771943519
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483576 SCV000568823 uncertain significance not provided 2021-03-02 criteria provided, single submitter clinical testing In-frame deletion of 2 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26809805, 24052634)
Invitae RCV000483576 SCV001232186 likely pathogenic not provided 2023-12-20 criteria provided, single submitter clinical testing This variant, c.81_86del, results in the deletion of 2 amino acid(s) of the COL4A4 protein (p.Ile29_Leu30del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs771943519, gnomAD 0.01%). This variant has been observed in individuals with autosomal dominant and recessive Alport syndrome and/or thin basement membrane nephropathy and hematuria (PMID: 24052634, 24854265, 26809805, 28632965, 28844315; Invitae). This variant is also known as p.Ile27_Ile29delinsIle. ClinVar contains an entry for this variant (Variation ID: 369962). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Molecular Genetics, Royal Melbourne Hospital RCV002225102 SCV002503863 likely pathogenic Autosomal recessive Alport syndrome 2023-03-30 criteria provided, single submitter clinical testing This sequence change is an inframe deletion of 6 bp predicted to cause the deletion of isoleucine and leucine at positions 29 and 30 of the COL4A4 protein (p.Ile29_Leu30del). The region deleted is moderately conserved (100 vertebrates, UCSC), and is located in a non-repeat region within the signal peptide. The variant is present in a large population cohort at a frequency of 0.005%, consistent with recessive disease (rs771943519, 14/280,560 alleles, 0 homozygotes in gnomAD v2.1.1 - PM2). It has been reported in at least four Alport syndrome cases with a second pathogenic COL4A4 allele (PMID: 24052634, 24854265, 28844315 - PM3_Strong), and heterozygous in at least two probands with a clinical diagnosis of thin basement membrane nephropathy (PMID: 26809805, 28844315). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PM2.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002225102 SCV002556063 likely pathogenic Autosomal recessive Alport syndrome 2022-06-22 criteria provided, single submitter clinical testing Variant summary: COL4A4 c.81_86delACTCAT (p.Ile29_Leu30del) results in an in-frame deletion that is predicted to remove two amino acids from exon 3 of the encoded protein. The variant allele was found at a frequency of 4.8e-05 in 249154 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in COL4A4 causing Alport Syndrome, Autosomal Recessive (4.8e-05 vs 0.0016), allowing no conclusion about variant significance. c.81_86delACTCAT has been reported in the literature in multiple compound heterozygous individuals affected with Alport Syndrome, including at least one case where it has been confirmed to be in trans with a pathogenic variant (e.g. Storey_2013, Moriniere_2014, Mallett_2017, Zhang_2021). These data indicate that the variant is very likely to be associated with disease. c.81_86delACTCAT has also been found in the heterozygous state in two individuals with thin basement membrane nephropathy (Weber_2016, Mallett_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five assessments for this variant have been submitted to ClinVar after 2014 with conflicting assessments (likely pathogenic n=2, VUS n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill RCV002284198 SCV002573570 uncertain significance Microscopic hematuria 2021-09-15 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000483576 SCV003834451 likely pathogenic not provided 2021-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV003352849 SCV004076581 likely pathogenic Inborn genetic diseases 2023-06-26 criteria provided, single submitter clinical testing The c.81_86delACTCAT (p.I29_L30del) alteration, located in exon 3 (coding exon 2) of the COL4A4 gene, results from an in-frame deletion of 6 nucleotides at positions 81 to 86. This results in the deletion of 2 amino acids between codons 29 and 30. Based on data from gnomAD, the c.81_86delACTCAT allele has an overall frequency of 0.005% (14/280560) total alleles studied. The highest observed frequency was 0.012% (3/24180) of African alleles. This variant has been reported in conjunction with a second COL4A4 variant in individuals with Alport syndrome and hematuric nephropathy (Storey, 2013; Morinière, 2014; Pinto E Vairo, 2021; Zhang, 2021); however, phase of the variants was not confirmed in most individuals. This variant was also detected with no second COL4A4 variant in individuals with hematuria and hematuric nephropathy (Morinière, 2014; Weber, 2016; Alge, 2023). Based on the available evidence, this alteration is classified as likely pathogenic.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare RCV000408829 SCV000484945 likely pathogenic Autosomal dominant Alport syndrome no assertion criteria provided clinical testing
Sydney Genome Diagnostics, Children's Hospital Westmead RCV001328063 SCV001449251 likely pathogenic Hematuria 2018-09-06 no assertion criteria provided clinical testing This patient is heterozygous for a known variant, c.81_86del (p.Ile29_Leu30del), in the COL4A4 gene. This variant results in the in-frame deletion of two residues p.Ile29 and p.Leu30, and has been previously reported in trans with another COL4A4 pathogenic variant in two patients with Alport syndrome (Storey et al 2013 J Am Soc Nephrol 24:1945-54). Storey et al considered this variant to be pathogenic.
Sydney Genome Diagnostics, Children's Hospital Westmead RCV001328130 SCV001449253 likely pathogenic Alport syndrome 2018-09-06 no assertion criteria provided clinical testing This patient is heterozygous for a known variant, c.81_86del (p.Ile29_Leu30del), in the COL4A4 gene. This variant results in the in-frame deletion of two residues p.Ile29 and p.Leu30, and has been previously reported in trans with another COL4A4 pathogenic variant in two patients with Alport syndrome (Storey et al 2013 J Am Soc Nephrol 24:1945-54). Storey et al considered this variant to be pathogenic.
Genomics England Pilot Project, Genomics England RCV001542735 SCV001760076 likely pathogenic Benign familial hematuria no assertion criteria provided clinical testing
Natera, Inc. RCV001328130 SCV002084181 uncertain significance Alport syndrome 2020-10-02 no assertion criteria provided clinical testing

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