ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.4793T>G (p.Leu1598Arg)

gnomAD frequency: 0.00001  dbSNP: rs752452590
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000665574 SCV000917259 pathogenic Autosomal recessive Alport syndrome 2025-04-10 criteria provided, single submitter clinical testing Variant summary: COL4A3 c.4793T>G (p.Leu1598Arg) results in a non-conservative amino acid change located in the Collagen IV, non-collagenous domain (IPR001442) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. At least one publication reports experimental evidence that this variant affects mRNA splicing (Deng_2022). The variant allele was found at a frequency of 5.6e-05 in 249436 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (5.6e-05 vs 0.0014), allowing no conclusion about variant significance. c.4793T>G has been reported in the literature in multiple individuals affected with Alport Syndrome, Autosomal Recessive (e.g., Oka_2014, Zhang_2021). 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: 24633401, 33772369, 35386907). ClinVar contains an entry for this variant (Variation ID: 550745). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000821858 SCV000962630 pathogenic not provided 2024-06-17 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1598 of the COL4A3 protein (p.Leu1598Arg). This variant is present in population databases (rs752452590, gnomAD 0.08%). This missense change has been observed in individual(s) with COL4A3-related conditions (PMID: 24633401). 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: 550745). 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 80%. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000665574 SCV001427110 pathogenic Autosomal recessive Alport syndrome 2020-07-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, caused by missense variants mostly glycine substitutions that affect the conformation of the protein, and loss of function, caused by either protein truncating and missense variants, are known mechanisms of disease in this gene and are associated with Alport syndrome and thin basement membrane nephropathy (PMID: 12028435, OMIM). (I) 0108 - This gene is associated with both recessive (Alport syndrome) and dominant disease (Alport syndrome and thin basement membrane nephropathy) (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01, East Asian subpopulation (15 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated C4 domain (NCBI, PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in patients with autosomal recessive Alport syndrome (ClinVar, PMID: 24633401). (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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Precision Medicine Center, Zhengzhou University RCV000665574 SCV001593071 uncertain significance Autosomal recessive Alport syndrome criteria provided, single submitter research PM1:Located in a mutational hot spot PM2:not found in gnomAD PP3:Multiple lines of computational evidence support a deleterious effect on the gene or gene product
Fulgent Genetics, Fulgent Genetics RCV005027778 SCV005656158 pathogenic Autosomal dominant Alport syndrome; Hematuria, benign familial, 2; Alport syndrome 3b, autosomal recessive 2024-03-21 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV005357888 SCV005914341 likely pathogenic Autosomal dominant Alport syndrome; Alport syndrome 3b, autosomal recessive 2023-02-23 criteria provided, single submitter research
Counsyl RCV000665574 SCV000789720 likely pathogenic Autosomal recessive Alport syndrome 2017-02-14 no assertion criteria provided clinical testing This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

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