ClinVar Miner

Submissions for variant NM_000092.5(COL4A4):c.1405G>T (p.Gly469Ter)

gnomAD frequency: 0.00001  dbSNP: rs926605269
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669401 SCV000794150 likely pathogenic Autosomal recessive Alport syndrome 2017-09-16 criteria provided, single submitter clinical testing
Molecular Genetics, Royal Melbourne Hospital RCV001788315 SCV002029248 pathogenic Autosomal dominant Alport syndrome 2021-11-11 criteria provided, single submitter clinical testing This sequence change in COL4A4 is a nonsense variant predicted to cause a premature stop codon (p.(Gly469*)) in biologically-relevant-exon 21/48 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 20301386). This variant is present in a single European (non-Finnish) individual in gnomAD v2.1 (1/67,998 alleles). This variant has been reported in at least two probands with a phenotype consistent with autosomal dominant Alport syndrome (PMID: 15954103; Royal Melbourne Hospital). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS4_Supporting, PM2_Supporting.
Invitae RCV002531228 SCV003525003 pathogenic not provided 2022-05-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly469*) in the COL4A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A4 are known to be pathogenic (PMID: 21196518, 24854265, 25307543). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Alport syndrome (PMID: 15954103). ClinVar contains an entry for this variant (Variation ID: 553870). 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.

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