Submissions for variant NM_000143.4(FH):c.1390+1G>T

dbSNP: rs886039367

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255853	SCV000321644	pathogenic	not provided	2018-08-21	criteria provided, single submitter	clinical testing	The c.1390+1G>T pathogenic variant in the FH gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor 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.1390+1G>T variant 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. We interpret c.1390+1G>T as a pathogenic variant.
Ambry Genetics	RCV001011336	SCV001171644	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-05-13	criteria provided, single submitter	clinical testing	The c.1390+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 9 of 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 the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript. As such, this alteration is classified as likely pathogenic.
Invitae	RCV000255853	SCV001576505	likely pathogenic	not provided	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change affects a donor 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 individual(s) with clinical features of fumarase deficiency (PMID: 27541980). ClinVar contains an entry for this variant (Variation ID: 265150). 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 variant disrupts the p.Tyr465 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12772087, 16597677; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Myriad Genetics, Inc.	RCV003454775	SCV004186955	likely pathogenic	Hereditary leiomyomatosis and renal cell cancer	2023-07-05	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Baylor Genetics	RCV001251427	SCV004197358	likely pathogenic	Fumarase deficiency	2023-05-29	criteria provided, single submitter	clinical testing
OMIM	RCV001251427	SCV001427035	pathogenic	Fumarase deficiency	2020-08-06	no assertion criteria provided	literature only