ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.3755C>T (p.Ala1252Val)

gnomAD frequency: 0.00008  dbSNP: rs761179248
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001562804 SCV001785630 uncertain significance not provided 2021-04-13 criteria provided, single submitter clinical testing Observed in a control group in published literature (Lucas et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease; This variant is associated with the following publications: (PMID: 29924831)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002265928 SCV002547820 uncertain significance not specified 2022-05-20 criteria provided, single submitter clinical testing Variant summary: COL4A3 c.3755C>T (p.Ala1252Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 249480 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (4.8e-05 vs 0.0019), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3755C>T in individuals affected with Alport Syndrome, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV002479226 SCV002781562 uncertain significance Autosomal dominant Alport syndrome; Autosomal recessive Alport syndrome; Benign familial hematuria 2022-04-22 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001562804 SCV004226014 uncertain significance not provided 2021-11-23 criteria provided, single submitter clinical testing PM2
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare RCV001029794 SCV001192573 likely benign Autosomal dominant Alport syndrome 2019-06-03 no assertion criteria provided clinical testing
Natera, Inc. RCV001832365 SCV002076424 uncertain significance Alport syndrome 2020-03-06 no assertion criteria provided clinical testing

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