ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.3210+1G>A

gnomAD frequency: 0.00001  dbSNP: rs1553762314
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000670389 SCV000795234 likely pathogenic Autosomal recessive Alport syndrome 2017-11-07 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001213668 SCV001385313 pathogenic not provided 2023-12-09 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 37 of the COL4A3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL4A3 are known to be pathogenic (PMID: 8956999, 24854265, 26809805, 27281700). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with autosomal recessive Alport syndrome (PMID: 24052634; Invitae). ClinVar contains an entry for this variant (Variation ID: 554710). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000670389 SCV001623348 likely pathogenic Autosomal recessive Alport syndrome 2021-04-19 criteria provided, single submitter clinical testing Variant summary: COL4A3 c.3210+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict that the variant abolishes a 5-prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 244902 control chromosomes. c.3210+1G>A has been reported in the literature in at least one individual affected with Alport Syndrome, Autosomal Recessive (e.g. Storey_2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002499171 SCV002813947 likely pathogenic Autosomal dominant Alport syndrome; Autosomal recessive Alport syndrome; Benign familial hematuria 2022-04-01 criteria provided, single submitter clinical testing
GeneDx RCV001213668 SCV005324972 pathogenic not provided 2023-04-05 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24052634)

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