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

dbSNP: rs771943519

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483576	SCV000568823	likely pathogenic	not provided	2024-12-18	criteria provided, single submitter	clinical testing	In-frame deletion of two 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: 24052634, 35759000, 28632965, 34758253, 36938085, 37248651, Kim2021[case report], 34746741, 28844315, 26809805, 33772369)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000483576	SCV001232186	likely pathogenic	not provided	2025-01-24	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; internal data). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001328130	SCV005399273	pathogenic	Alport syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function is a known mechanism of disease for this gene and is associated with COL4A4-related nephropathy. Dominant negative is a suspected mechanism of disease for this gene as it is a structural protein (PMIDs: 12028435, 24046192). (I) 0108 - This gene is associated with both recessive and dominant disease. Alport syndrome typically has biallelic inheritance, although rare cases of monoallelic inheritance have been reported (PMID: 28704582). TBMN and focal segmental glomerulosclerosis (FSGS) are associated with autosomal dominant inheritance (OMIM, PMIDs: 16467446, 17942953). (I) 0216 - In-frame deletion in a non-repetitive region that has low conservation. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a condition (14 heterozygotes, 0 homozygotes). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in over ten individuals with COL4A4-related nephropathy, and has been associated with both AR and AD forms of disease (ClinVar, LOVD, PMIDs: 28844315, 24854265, 26809805, 24052634, 33772369). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV000483576	SCV005413561	pathogenic	not provided	2024-03-14	criteria provided, single submitter	clinical testing	PM2, PM3_strong, PM4, PS4
3billion	RCV002225102	SCV005904066	likely pathogenic	Autosomal recessive Alport syndrome	2023-06-30	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Predicted Consequence/Location: Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000369962 /PMID: 24052634). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV002225102	SCV005914344	likely pathogenic	Autosomal recessive Alport syndrome	2023-03-06	criteria provided, single submitter	research
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