Submissions for variant NM_000091.5(COL4A3):c.441G>A (p.Pro147=)

gnomAD frequency: 0.00001  dbSNP: rs373559251

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519854	SCV000621575	uncertain significance	not provided	2025-02-04	criteria provided, single submitter	clinical testing	In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV005004215	SCV000895397	likely pathogenic	Autosomal dominant Alport syndrome; Hematuria, benign familial, 2; Alport syndrome 3b, autosomal recessive	2024-02-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000519854	SCV003462202	likely pathogenic	not provided	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change affects codon 147 of the COL4A3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL4A3 protein. This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. This variant is present in population databases (rs373559251, gnomAD 0.006%). This variant has been observed in individuals with clinical features of autosomal dominant Alport syndrome and Thin Basement Membrane Nephropathy [TBMN] (internal data). ClinVar contains an entry for this variant (Variation ID: 452744). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782424	SCV005394534	uncertain significance	not specified	2024-09-12	criteria provided, single submitter	clinical testing	Variant summary: COL4A3 c.441G>A (p.Pro147Pro) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes or weakens a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 249264 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.441G>A in individuals affected with Alport Syndrome, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 452744). Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000519854	SCV005877608	uncertain significance	not provided	2024-08-08	criteria provided, single submitter	clinical testing	The COL4A3 c.441G>A; p.Pro147Pro variant (rs373559251), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 452744). This variant is found in the general population with an overall allele frequency of 0.002% (7/280,648 alleles) in the Genome Aggregation Database (v2.1.1). This is a synonymous variant and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Due to limited information, the clinical significance of this variant is uncertain at this time.
Natera, Inc.	RCV001272224	SCV001454001	uncertain significance	Alport syndrome	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003419915	SCV004118282	uncertain significance	COL4A3-related disorder	2024-09-02	no assertion criteria provided	clinical testing	The COL4A3 c.441G>A variant is not predicted to result in an amino acid change (p.=). This variant is located at the last nucleotide of the exon and is predicted to abolish the canonical donor splice site (Alamut Visual Plus v1.6.1). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0057% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.