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

gnomAD frequency: 0.00001  dbSNP: rs752452590

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665574	SCV000789720	likely pathogenic	Autosomal recessive Alport syndrome	2017-02-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000665574	SCV000917259	likely pathogenic	Autosomal recessive Alport syndrome	2019-07-01	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. The variant allele was found at a frequency of 5.6e-05 in 249436 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in COL4A3 causing Alport Syndrome, autosomal recessive (5.6e-05 vs 0.002), allowing no conclusion about variant significance. c.4793T>G has been reported in the literature in at-least 5 individuals affected with autosomal recessive Alport Syndrome in compound heterozygosity (Oka_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One other submitter has provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000821858	SCV000962630	pathogenic	not provided	2024-01-17	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	RCV001251486	SCV001427110	uncertain significance	Autosomal dominant Alport syndrome	2018-05-15	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_000091.4(COL4A3):c.4793T>G, has been identified in exon 51 of 52 of the COL4A3 gene. The variant is predicted to result in a major amino acid change from leucine to arginine at position 1598 of the protein (NP_000082.2(COL4A3):p.(Leu1598Arg)). The leucine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the C4 domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.005% (0 homozygotes). This variant has not been previously reported in clinical cases. Based on the information available at the time of curation, this variant has been classified as VARIANT of UNCERTAIN SIGNIFICANCE (VUS).
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