Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000493531 | SCV000581665 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-07-20 | criteria provided, single submitter | clinical testing | The c.905-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 7 of the FH gene. In one study, this mutation was identified in four Iranian families with multiple cutaneous and uterine leiomyomas, and haplotype analysis suggested this alteration may represent a founder mutation (Chuang GS et al. J. Am. Acad. Dermatol. 2005 Mar;52:410-6). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. In addition to the clinical data presented in the literature, 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. |
Labcorp Genetics |
RCV001534141 | SCV000944048 | pathogenic | not provided | 2023-08-03 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as 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: 208374). Disruption of this splice site has been observed in individual(s) with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) (PMID: 15761418). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 6 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). |
Baylor Genetics | RCV000804152 | SCV001162886 | pathogenic | Fumarase deficiency | 2024-03-11 | criteria provided, single submitter | clinical testing | |
Gene |
RCV001534141 | SCV001751041 | likely pathogenic | not provided | 2021-06-14 | criteria provided, single submitter | clinical testing | Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 27535533, 15761418, 20301430, 20618355, 17908262, 15663510, 19939761, 25525159) |
Gene |
RCV000193655 | SCV000244289 | not provided | Hereditary leiomyomatosis and renal cell cancer | no assertion provided | literature only |