ClinVar Miner

Submissions for variant NM_000143.3(FH):c.1431_1433dup (p.Lys477dup) (rs367543046)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164180 SCV000214800 likely pathogenic Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous,Other data supporting pathogenic classification
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034483 SCV000043258 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000034483 SCV000224779 pathogenic not provided 2015-01-20 criteria provided, single submitter clinical testing
GeneDx RCV000034483 SCV000251462 uncertain significance not provided 2018-08-20 criteria provided, single submitter clinical testing This in-frame duplication of three nucleotides in FH is denoted c.1431_1433dupAAA at the cDNA level and p.Lys477dup (K477dup) at the protein level. Using alternate nomenclature, this variant has also been described as 1302insAAA, Lys434ins, insK477, 435insK, and 435insAAA. The normal sequence, with the bases that are duplicated in brackets, is ACAA[dupAAA]TGGA. FH Lys477dup was observed at an allele frequency of 0.50% (51/10,146) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This duplication of a single Lysine residue occurs at a position that is conserved across species and is not located in a known functional domain. FH Lys477dup has been observed in the compound heterozygous state in multiple patients with fumarate hydratase deficiency (FHD) (Rustin 1997, Coughlin 1998, Loeffen 2005, Pollard 2005, Deschauer 2006, Ottolenghi 2011, Ezgu 2013, Tregoning 2013, Prasad 2017). However, several individuals homozygous for Lys477dup without reported features of FHD have been observed both internally and in large population cohorts. While cells that are compound heterozygous for FH Lys477dup and other FH variants show significantly reduced fumarate hydratase enzyme activity (Pollard 2005, Raimundo 2008), there are no data, to our knowledge, that demonstrate the functional effects of FH Lys477dup alone. To our knowledge, only one relative of a patient with FHD who was heterozygous for Lys477dup was reported as having features of hereditary leiomyomatosis and renal cell cancer (HLRCC), and there are limited reports of this variant in individuals with renal cell carcinoma or leiomyomas (Ezgu 2013, Chen 2014, Martinek 2015). Additionally, this variant has been identified in multiple individuals without HLRCC (Ylikaukko-oja 2006, Mandelker 2017, Pritchard 2018, Whitworth 2018). Therefore, based on currently available evidence, we consider FH Lys477dup to be a variant of uncertain significance.
GeneReviews RCV000034921 SCV000058528 pathologic Fumarase deficiency 2013-04-04 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000034921 SCV000283665 likely pathogenic Fumarase deficiency 2019-01-02 criteria provided, single submitter clinical testing This sequence change inserts 3 nucleotides in exon 10 of the FH mRNA (c.1431_1433dupAAA). This leads to the insertion of 1 amino acid residue in the FH protein (p.Lys477dup) but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs367543046, ExAC 0.1%). This variant has been observed in combination with other pathogenic FH variants in multiple individuals with autosomal recessive fumarate hydratase deficiency (FHD) (PMID: 9300800, 9635293, 23612258, 16510303, 16151915, 24182348, 27541980, Invitae). However, individuals who are homozygous for this variant do not have clinical features of FHD (gnomAD, Invitae, external communication). It has also been observed as heterozygous in a few individuals with features suggestive of autosomal dominant hereditary leiomyomatosis and renal cell cancer (HLRCC), as well as in unaffected controls (PMID: 23612258, 16639410, 24441663, 25985877, 22703879, Invitae). This variant is also known as c.1433_1434insAAA, c.1431insAAA, c.1433_1434dupAAA, AAAins435, 435insK, InsK477, and 435insAAA in the literature. ClinVar contains an entry for this variant (Variation ID: 42095). Experimental studies have shown that patient cells carrying this variant and another loss-of-function FH variant have significantly reduced fumarate hydratase enzyme activity (0-20%), compared to wild-type cells (PMID: 9300800, 9635293, 15987702, 16151915, 24182348). No in vitro functional studies measuring the enzymatic activity of this variant alone have been performed. In summary, this is an in-frame duplication that has been observed with several different pathogenic FH variants in multiple affected individuals with FHD. In the homozygous state, this variant does not likely cause FHD, but additional data are needed to prove that conclusively. Although it has been observed as heterozygous in individuals with features of HLRCC, it occurs in the general population too frequently given the rarity of this condition. For these reasons, this variant has been classified as Likely Pathogenic for FHD. However, it is not likely to confer risk for HLRCC.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.