Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000198930 | SCV000251483 | pathogenic | not provided | 2014-07-30 | criteria provided, single submitter | clinical testing | IVS9-2 A>T; c.1391-2 A>T. The c.1391-2 A>T splice site mutation in the FH gene destroys the canonical splice acceptor site in intron 9. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1391-2 A>T mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although this mutation has not been previously reported to our knowledge, its presence is consistent with a diagnosis of hereditary leiomyomatosis and renal cell cancer. The variant is found in FH panel(s). |
| Ambry Genetics | RCV000494502 | SCV000581675 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-03-21 | criteria provided, single submitter | clinical testing | The c.1391-2A>T intronic variant results from an A to T substitution two nucleotides upstream from coding exon 10 in the FH gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish and significantly weaken the native splice acceptor site; however, direct evidence is unavailable. This alteration, as well as a close match alteration - FH c.1391-2A>T- have been observed in individuals who have a personal and/or family history that is consistent with FH-associated disease (Ambry internal data; Muller M et al. Clin. Genet., 2017 Dec;92:606-615). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the majority of available evidence, this alteration is classified as a disease-causing mutation. |
| Labcorp Genetics |
RCV000198930 | SCV002216362 | pathogenic | not provided | 2021-11-08 | criteria provided, single submitter | clinical testing | 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. This sequence change affects an acceptor splice site in intron 9 of the FH gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of hereditary leiomyomatosis and renal cell cancer (PMID: 28266706, 28300276; Invitae). ClinVar contains an entry for this variant (Variation ID: 214423). For these reasons, this variant has been classified as Pathogenic. |
| Baylor Genetics | RCV004567403 | SCV005057773 | likely pathogenic | Fumarase deficiency | 2023-12-28 | criteria provided, single submitter | clinical testing |