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

gnomAD frequency: 0.00001  dbSNP: rs752452590

Total submissions: 7

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 [e-mail].