Submissions for variant NM_000091.5(COL4A3):c.3546_3548dup (p.Gly1183dup)

dbSNP: rs1175052474

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626593	SCV000747294	pathogenic	Proteinuria; Microscopic hematuria; Moderate albuminuria	2017-01-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626594	SCV000747295	likely pathogenic	Macroscopic hematuria	2017-01-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000505632	SCV001369701	pathogenic	Autosomal dominant Alport syndrome	2019-10-11	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000681705	SCV001485870	likely pathogenic	not provided	2024-11-05	criteria provided, single submitter	clinical testing	This variant, c.3546_3548dup, results in the insertion of 1 amino acid(s) of the COL4A3 protein (p.Gly1183dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Alport syndrome (PMID: 30586318; internal data). ClinVar contains an entry for this variant (Variation ID: 438655). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
GeneDx	RCV000681705	SCV001983267	likely pathogenic	not provided	2024-12-16	criteria provided, single submitter	clinical testing	In-frame duplication of 1 amino acid in the triple helical domain; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36117978, 30586318)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000505632	SCV002764995	likely pathogenic	Autosomal dominant Alport syndrome	2022-07-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000681705	SCV004811563	likely pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	COL4A3: PM1, PM2, PM4:Supporting, PS4:Supporting
Fulgent Genetics, Fulgent Genetics	RCV005027584	SCV005656075	likely pathogenic	Autosomal dominant Alport syndrome; Hematuria, benign familial, 2; Alport syndrome 3b, autosomal recessive	2024-02-23	criteria provided, single submitter	clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000505632	SCV000599808	pathogenic	Autosomal dominant Alport syndrome	2019-10-31	no assertion criteria provided	clinical testing
Gharavi Laboratory, Columbia University	RCV000681705	SCV000809157	likely pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Natera, Inc.	RCV001834631	SCV002076419	uncertain significance	Alport syndrome	2020-03-03	flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003915403	SCV004732621	likely pathogenic	COL4A3-related disorder	2024-02-14	no assertion criteria provided	clinical testing	The COL4A3 c.3546_3548dupAGG variant is predicted to result in an in-frame duplication (p.Gly1183dup). This variant has been reported in the heterozygous state in an individual with glomerulopathy (Table S7, Groopman et al. 2019. PubMed ID: 30586318). In addition, at PreventionGenetics, we have previously found this variant in the heterozygous state in an individual tested for the nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) panel. This one amino acid duplication variant occurs at the conserved triple helical domain (residues 43-1438) of the COL4A3 protein (uniprot.org), where substitutions of the glycine (Gly) residue are usually pathogenic (Hudson et al. 1993. PubMed ID: 8253711; https://www.ncbi.nlm.nih.gov/books/NBK1207/). The consequence of this glycine duplication variant is expected to disturb the conserved triple helical Gly-X-Y repeats; and the same type of one amino acid duplication/insertion variant at a different but nearby location has been reported in an individual with isolated hematuria (c.3547_3548insGGA resulting in p.Gly1183_Asn1184insArg at Slajpah et al. 2007. PubMed ID: 17396119). The p.Gly1183dup variant is interpreted as likely pathogenic.