Submissions for variant NM_000091.5(COL4A3):c.765G>A (p.Thr255=)

gnomAD frequency: 0.00001  dbSNP: rs869025328

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000256383	SCV000798581	uncertain significance	Autosomal recessive Alport syndrome	2018-03-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764364	SCV000895398	uncertain significance	Autosomal dominant Alport syndrome; Autosomal recessive Alport syndrome; Benign familial hematuria	2018-10-31	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000735673	SCV001367207	uncertain significance	Autosomal dominant Alport syndrome	2018-11-07	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001859498	SCV002281146	likely pathogenic	not provided	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change affects codon 255 of the COL4A3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL4A3 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has been observed in individual(s) with Alport syndrome (PMID: 35386907). 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: 266006). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of 13, but is expected to preserve the integrity of the reading-frame (PMID: 35386907). 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.
3billion	RCV000735673	SCV003841849	uncertain significance	Autosomal dominant Alport syndrome	2023-02-23	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: <0.001%). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.90). The variant has been reported to be associated with COL4A3 -related Alport syndrome (PMID: 34120753). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV001859498	SCV005327852	likely pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	Reported in multiple patients with COL4A3-related renal disease in published literature (PMID: 34120753, 34746741); Non-canonical splice site variant within a critical functional domain, the triple helical region; alters the last nucleotide of the exon and is predicted to damage the splice donor site but the effect on protein function is unclear; Published in vitro functional studies suggest a deleterious effect on splicing, concordant with RNA testing performed at GeneDx (PMID: 35386907); Internal targeted RNA studies in blood from a different patient referred for testing at GeneDx demonstrate this variant causes abnormal RNA splicing by damaging the natural splice donor site in intron 13 and causing the skipping of exon 13, which is predicted to result in the in-frame deletion of 26 amino acids encoding a portion of a critical functional domain (triple helical domain); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35386907, 34746741, 35121647, 38188341, 34120753)
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000256383	SCV000323165	uncertain significance	Autosomal recessive Alport syndrome		no assertion criteria provided	clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000735673	SCV000863816	pathogenic	Autosomal dominant Alport syndrome	2018-02-19	no assertion criteria provided	clinical testing