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

dbSNP: rs367543046

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164180	SCV000214800	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-07	criteria provided, single submitter	clinical testing	The c.1431_1433dupAAA pathogenic mutation (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 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; Forde C et al. Eur Urol Oncol., 2020 12;3(6):764-772; Pahl L et al. Pediatr Blood Cancer., 2018 10;65(10):e27254; 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 alteration is interpreted as a disease-causing mutation in the compound heterozygous state in association with FH deficiency; however, it is not considered a risk factor for HLRCC.
Eurofins Ntd Llc (ga)	RCV000034483	SCV000224779	pathogenic	not provided	2015-01-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000034483	SCV000251462	pathogenic	not provided	2023-07-10	criteria provided, single submitter	clinical testing	In-frame duplication of 1 amino acid in a non-repeat region; Recent studies suggest that in the heterozygous state, this variant is not associated with an increased risk to develop HLRCC-related tumors (Zhang et al., 2020; Gupta et al., 2021; Kamihara et al., 2021); This variant has been observed as homozygous in asymptomatic adults tested at GeneDx and in large population cohorts (gnomAD; internal data), suggesting this variant is not associated with FHD when present in the homozygous state; In silico analysis supports a deleterious effect on protein structure/function; Also known as 1302insAAA, Lys434ins, insK477, 435insK, and 435insAAA; This variant is associated with the following publications: (PMID: 28748451, 27051561, 23612258, 2314594, 29319699, 31942411, 31831373, 16151915, 9300800, 9635293, 15987702, 20301679, 27621404, 20549362, 28873162, 29506128, 12761039, 16237213, 28825054, 29641532, 22703879, 18313410, 25985877, 16639410, 21560188, 24441663, 24182348, 16510303, 27541980, 30256826, 29909963, 30426508, 31212687, 28552549, 31444830, 32782288, 31980526, 32581362, 33789101, 33166576, 32413184, 32012241, 33363901, 35626031, 34308104, 35441217, 34289891, 33858029, 31794323, 34994643, 34337822, 35993574, 36556183, 32999401, 29893455, 36773955, 36777509, 33439686, 37255402, 36947458)
Invitae	RCV000034483	SCV000283665	likely pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This variant, c.1431_1433dup, results in the insertion of 1 amino acid(s) of the FH protein (p.Lys477dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs367543046, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. 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. ClinVar contains an entry for this variant (Variation ID: 42095). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. 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.
Baylor Genetics	RCV000034921	SCV001162885	pathogenic	Fumarase deficiency		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034483	SCV001247136	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	FH: PS4, PP4:Moderate, PS3:Moderate, PM2:Supporting, PM4:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001000649	SCV001363564	uncertain significance	not specified	2023-04-24	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, Carlo_2020, Hartman_2020), 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). However, two recent studies provide evidence that c.1431_1433dupAAA is not associted with Renal Cell Cancer (RCC): in a large US cancer cohort of 7571 patients, none of the renal cell cancer patients carried the variant of interest (Zhang_2020). In a following case study of 2 carriers with renal cell carcinoma, immunohistochemistry-based analysis of patient tumors revealed no FH-deficiency with the authors concluding that this variant may not contribute to RCC (Gupta_2021). 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. Seventeen ClinVar submitters have assessed the variant since 2014: one classified the variant as likely benign, five as uncertain significance, four as likely pathogenic, and seven as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic for 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
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034483	SCV002010134	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000034483	SCV002022987	pathogenic	not provided	2023-03-29	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000034483	SCV002051723	uncertain significance	not provided	2021-01-28	criteria provided, single submitter	clinical testing	PM3, PM4
Genetic Services Laboratory, University of Chicago	RCV000034483	SCV002070473	likely pathogenic	not provided	2020-03-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FH gene demonstrated a three base pair duplication in exon 10, c.1431_1433dup. This pathogenic sequence change results in the duplication of one amino acid residue, p.Lys477dup. The p.Lys477dup sequence change is the most frequent mutant allele observed in patients with autosomal recessive FH-associated fumarate hydratase deficiency (PMID: 20301679). Functional studies have shown that the p.Lys477dup sequence change leads to significantly reduced FH enzyme activity levels (PMID: 15987702).
Mendelics	RCV001762110	SCV002516370	pathogenic	Hereditary leiomyomatosis and renal cell cancer	2022-05-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164180	SCV002535543	likely benign	Hereditary cancer-predisposing syndrome	2021-11-02	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001000649	SCV002552125	uncertain significance	not specified	2022-07-30	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV001762110	SCV002581813	likely pathogenic	Hereditary leiomyomatosis and renal cell cancer	2022-08-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034483	SCV002774595	uncertain significance	not provided	2023-04-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415765	SCV004114759	likely pathogenic	FH-related condition	2024-01-04	criteria provided, single submitter	clinical testing	The FH c.1431_1433dupAAA variant is predicted to result in an in-frame duplication (p.Lys477dup). This variant has been reported in the heterozygous state in individuals with hereditary leiomyomatosis and renal cell cancer (Chen et al. 2014. PubMed ID: 24441663; Martínek et al. 2015. PubMed ID: 25985877); however it has also been observed in many unaffected individuals (Ylisaukko-oja et al. 2006. PubMed ID: 16639410; Johnston et al. 2012. PubMed ID: 22703879, Table S1; Zhang et al. 2020. PubMed ID: 31444830). In the gnomAD database, this variant has been observed in the Ashkenazi Jewish population at an allele frequency of 0.5%, and it is documented in two homozygous individuals in gnomAD. This duplication has been reported as causative for autosomal recessive fumarase deficiency when found in the compound heterozygous state with a second pathogenic FH variant, but has not been documented as causative in the homozygous state (Rustin et al. 1997. PubMed ID: 9300800; Coughlin et al. 1998. PubMed ID: 9635293; Deschauer et al. 2006. PubMed ID: 16510303; Tregoning S et al 2013. PubMed ID: 24182348). In ClinVar, this variant is reported as uncertain significance, likely pathogenic, and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/42095/) . We classify the FH c.1431_1433dup (p.Lys477dup) variant as likely pathogenic in the context of fumarase deficiency, when found in the compound heterozygous state. The c.1431_1433dup (p.Lys477dup) variant in the homozygous state, is less likely to contribute to disease. This variant is unlikely to be pathogenic for hereditary leiomyomatosis and renal cell cancer and in the context of autosomal dominant phenotypes, this alteration is classified as a variant of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034483	SCV004562079	likely pathogenic	not provided	2023-09-14	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: https://www.ncbi.nlm.nih.gov/books/NBK1506/ 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.
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	not provided	Fumarase deficiency		no assertion provided	literature only
OMIM	RCV000034921	SCV001427034	pathogenic	Fumarase deficiency	2020-08-07	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000034483	SCV001807422	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000034483	SCV001958435	pathogenic	not provided		no assertion criteria provided	clinical testing