ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1021G>A (p.Asp341Asn) (rs11545655)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000472953 SCV000544262 likely pathogenic Fumarase deficiency 2017-07-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 341 of the FH protein (p.Asp341Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in a family with two affected individuals, and an affected individual with papillary type 2 renal cell carcinoma (PMID: 24684806, 21304509). It has been also observed as a germline variant in individuals with nonsyndromic uterine leiomyomas, many of whom had a family history of uterine leimyomas (PMID: 22528940). Experimental studies have shown that tumor cells from an affected individual carrying this variant has a significant reduction in fumarate hydratase enzyme activity as well as a loss of the wild-type FH allele. In addition, this variant disrupts the formation of FH tetrameric complexes in vitro (PMID: 21304509). In summary, this variant is a rare missense change that has been shown to affect protein function and has been observed in a family and multiple individuals affected with FH-related disease. In the absence of additional genetic/functional evidence, it has been classified as Likely Pathogenic.

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