ClinVar Miner

Submissions for variant NM_000143.4(FH):c.1431_1433dup (p.Lys477dup) (rs367543046)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164180 SCV000214800 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-07 criteria provided, single submitter clinical testing The c.1431_1433dupAAA variant (also known as p.K477dup), located in coding exon 10 of the FH gene, results from an in-frame duplication of AAA at nucleotide positions 1431 to 1433. This results in the duplication of an extra lysine residue at codon 477. This alteration has been identified in a suspected or confirmed compound heterozygous state with other FH alterations in numerous children with autosomal recessive fumarate hydratase (FH) deficiency syndrome (Gellera C et al. Neurology 1990 Mar;40:495-9; Rustin P et al. Biochim. Biophys. Acta 1997 Aug;1361:185-97; Coughlin EM et al. Mol. Genet. Metab. 1998 Apr;63:254-62; Loeffen J et al. J. Inherit. Metab. Dis. 2005;28:799-800; Pollard PJ et al. Hum. Mol. Genet. 2005 Aug;14:2231-9; Deschauer M et al. Mol. Genet. Metab. 2006 Jun;88:146-52, Ottolenghi C et al. Hum. Mutat. 2011 Sep;32:1046-52; Ezgu F et al. Gene 2013 Jul;524:403-6; Tregoning S et al. Twin Res. Hum. Genet. 2013 Dec;16:1117-20). However, this variant has been detected incidentally in a homozygous state in individuals who do not have features that are consistent with FH deficiency, although they may not have been ascertained for FH-related diseases (Ambry internal data). A cell line derived from an FH deficiency patient who is compound heterozygous for this alteration and FH p.R233H showed defective energy and redox metabolism at the mRNA level (Raimundo N et al. Biochim. Biophys. Acta 2008 May;1782:287-94). In the literature, this variant has been detected in a heterozygous state in a few individuals who have some features that are consistent with autosomal dominant HLRCC including renal cancer, uterine leiomyomas and subcutaneous leiomyomas, although at least one of these individuals carried another FH alteration (phase unknown) (Chen YB et al. Am. J. Surg. Pathol. 2014 May;38:627-37; Martínek P et al. Virchows Arch. 2015 Aug;467:185-91; Ylisaukko-oja SK et al. Eur. J. Hum. Genet. 2006 Jul;14:880-3; Ezgu F et al. Gene 2013 Jul;524:403-6). However, this variant has also been detected in a heterozygous state in a vast number of individuals who do not have a personal or family history that is consistent with or suggestive of HLRCC (Zhang L et al. Hum. Mutat., 2020 Jan;41:103-109; Ambry internal data). Of note, this alteration is also designated as K434ins, c.1302insAAA, c.1433dupAAA, AAAins435, 435insK, 435insAAA, c.1433_1434dupAAA, and c.1431insAAA in published literature. Based on the majority of available evidence to date, this variant is likely to be pathogenic in the compound heterozygous state in association with FH deficiency; however, it is not considered a risk factor for HLRCC.
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.
Invitae RCV000034921 SCV000283665 likely pathogenic Fumarase deficiency 2020-11-02 criteria provided, single submitter clinical testing This sequence change inserts 3 nucleotides in exon 10 of the FH mRNA (c.1431_1433dup). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000649 SCV001157674 likely pathogenic not specified 2019-03-07 criteria provided, single submitter clinical testing The FH c.1431_1433dupAAA; p.Lys477dup variant (rs367543046), also known as Lys434ins, 1302insAAA, 1431insAAA, 1433_1434dupAAA, is commonly found in the compound heterozygous state in individuals with fumarase deficiency (Coughlin 1998, Ezgu 2013, Rustin 1997), and is considered the most frequent pathogenic variant associated with fumarase deficiency (Ewbank 2013). It is also reported in the heterozygous state in individuals with cancer predisposition syndrome including hereditary leiomyomatosis and renal cell cancer syndrome (Chen 2014, Ezgu 2013, Martinek 2015, Whitworth 2018). This variant is reported in ClinVar (Variation ID: 42095). It is found in the general population with an overall allele frequency of 0.1% (285/280892 alleles, including 2 homozygotes) in the Genome Aggregation Database. Based on available information, this variant is considered to be likely pathogenic. REFERENCES Chen YB et al. Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry. Am J Surg Pathol. 2014 May;38(5):627-37. Coughlin EM et al. Molecular analysis and prenatal diagnosis of human fumarase deficiency. Mol Genet Metab. 1998 Apr;63(4):254-62. Ewbank C et al. Fumarate Hydratase Deficiency. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. SourceGeneReviews (Internet). Seattle (WA): University of Washington, Seattle; 1993-2019. 2006 Jul 5 (updated 2013 Apr 4). Accessed online at: Ezgu F et al. Mild clinical presentation and prolonged survival of a patient with fumarase deficiency due to the combination of a known and a novel mutation in FH gene. Gene. 2013 Jul 25;524(2):403-6. Martinek P et al. Genetic testing of leiomyoma tissue in women younger than 30 years old might provide an effective screening approach for the hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC). Virchows Arch. 2015 Aug;467(2):185-91. Rustin P et al. Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human. Biochim Biophys Acta. 1997 Aug 22;1361(2):185-97. Whitworth J et al. Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes. Am J Hum Genet. 2018 Jul 5;103(1):3-18.
Baylor Genetics RCV000034921 SCV001162885 pathogenic Fumarase deficiency criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034483 SCV001247136 uncertain significance not provided 2019-12-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001000649 SCV001363564 uncertain significance not specified 2019-12-23 criteria provided, single submitter clinical testing Variant summary: FH c.1431_1433dupAAA (p.Lys477dup) results in a duplication of a lysine residue in the Fumarase C, C-terminal domain (IPR018951) of the encoded protein sequence. The variant allele was found at a frequency of 0.001 in 249492 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 415 fold of the estimated maximal expected allele frequency for a pathogenic variant in FH causing Hereditary Leiomyomatosis and Renal Cell Cancer phenotype (2.5e-06), strongly suggesting that the variant is benign. Due to its high frequency, c.1431_1433dupAAA has been reported in the literature in multiple individuals affected with features of Hereditary Leiomyomatosis and Renal Cell Cancer (example, Ezgu_2013, Ylisaukko-oja_2006, BeiChen_2014, Martinek_2015), multiple primary tumors (Whitworth_2018), in a study examining cancer susceptibility variants in subjects with atherosclerosis phenotypes (ClinSeq cohort, Johnston_2012) and in compound heterozygous genotypes with other FH variants in case reports of patients with biochemically and clinically confirmed Fumarase deficiency (example, Tregoning_2013, Deschauer_2006, Loeffen_2005, Coughlin_1998, Prasad_2017). To our knowledge, no homozygous patients affected with classic Fumarase deficiency have been ascertained. In 2002, the Multiple Leiomyoma Consortium identified FH as a non-classical tumor suppressor gene responsible for multiple cutaneous and uterine leiomyomas (MCUL) as well as hereditary leiomyomatosis and renal cell cancer (HLRCC) (as cited in Ezgu_2013). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on FH activity in compound heterozygous genotypes (example, Tregoning_2013, Loeffen_2005, Pollard_2005, Coughlin_1998). However, these reports do not allow convincing conclusions about the variant effect due to lack of homozygous control activity measurements. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Some of them cite multiple overlapping publications utilized in the context of this evaluation. Two of these laboratories have classified the variant as likely pathogenic, while one laboratory has recently re-classified this variant from its current clinVar classification of pathogenic to a VUS (Emory database), and another has classified it as a VUS. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic due to possible risk for HLRCC in carriers of this variant as well as Fumarase deficiency when observed in combination with other pathogenic/likely pathogenic variants in the FH gene.
Institute of Human Genetics, University of Leipzig Medical Center RCV000034921 SCV001428620 uncertain significance Fumarase deficiency 2017-04-25 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000034483 SCV001715674 uncertain significance not provided 2020-07-16 criteria provided, single submitter clinical testing
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.
GeneReviews RCV000034921 SCV000058528 pathologic Fumarase deficiency 2013-04-04 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000034921 SCV001427034 pathogenic Fumarase deficiency 2020-08-07 no assertion criteria provided literature only

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