ClinVar Miner

Submissions for variant NM_000143.4(FH):c.133-3T>C

gnomAD frequency: 0.00001  dbSNP: rs1553341989
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001698486 SCV000727689 likely benign not provided 2021-04-19 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001698486 SCV000832068 uncertain significance not provided 2024-01-19 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the FH gene. It does not directly change the encoded amino acid sequence of the FH protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FH-related conditions. ClinVar contains an entry for this variant (Variation ID: 515546). 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 is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV001011105 SCV001171387 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-22 criteria provided, single submitter clinical testing The c.133-3T>C intronic variant results from a T to C substitution 3 nucleotides upstream from coding exon 2 in the FH gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing; however, direct evidence is insufficient (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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