Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002563184 | SCV001402905 | likely pathogenic | not provided | 2022-08-22 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 957443). Disruption of this splice site has been observed in individual(s) with clinical features of FH-related conditions (PMID: 30741757). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 3 of the FH 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 FH are known to be pathogenic (PMID: 11865300, 21398687). |
| Ambry Genetics | RCV002366032 | SCV002625770 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-02-22 | criteria provided, single submitter | clinical testing | The c.378+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 3 of the FH gene. This alteration has been observed in individuals with a personal and/or family history that is consistent with FH-related disease (Taniguchi R et al. Fam Cancer. 2022 Jul;21(3):337-341; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration impacting the same donor site (c.378G>C) has been described in a patient with histopathologically confirmed cutaneous leiomyomas (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. As such, this alteration is classified as a disease-causing mutation. |
| Baylor Genetics | RCV003469407 | SCV004197318 | likely pathogenic | Fumarase deficiency | 2023-09-21 | criteria provided, single submitter | clinical testing |