ClinVar Miner

Submissions for variant NM_000143.3(FH):c.738+2T>C (rs1060500901)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000458630 SCV000917375 likely pathogenic Fumarase deficiency 2018-02-27 criteria provided, single submitter clinical testing Variant summary: FH c.738+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 245936 control chromosomes. To our knowledge, no occurrence of c.738+2T>C in individuals affected with Hereditary Leiomyomatosis and Renal Cell Cancer and no experimental evidence demonstrating its impact on protein function have been reported. However, a different change at the same nucleotide (c.738+2T>A) has been reported in a patient affected with multiple cutaneous leiomyomas. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000458630 SCV000544260 pathogenic Fumarase deficiency 2018-12-10 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the FH gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individuals affected with multiple cutaneous leiomyomas and/or renal cell carcinoma (PMID: 28300276, 26173633, Invitae). Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic.

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