1-241497927-AT-ATTTT
Variant summary
Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PM1PM4_SupportingPP5BS1_SupportingBS2
The NM_000143.4(FH):c.1431_1433dupAAA(p.Lys477dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,613,964 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N478N) has been classified as Likely benign.
Frequency
Consequence
NM_000143.4 disruptive_inframe_insertion
Scores
Clinical Significance
Conservation
Publications
- hereditary leiomyomatosis and renal cell cancerInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
- fumaric aciduriaInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
- pheochromocytoma-paragangliomaInheritance: AD Classification: STRONG Submitted by: Ambry Genetics
- leiomyosarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary pheochromocytoma-paragangliomaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -1 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000143.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| FH | NM_000143.4 | MANE Select | c.1431_1433dupAAA | p.Lys477dup | disruptive_inframe_insertion | Exon 10 of 10 | NP_000134.2 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| FH | ENST00000366560.4 | TSL:1 MANE Select | c.1431_1433dupAAA | p.Lys477dup | disruptive_inframe_insertion | Exon 10 of 10 | ENSP00000355518.4 | ||
| FH | ENST00000493477.2 | TSL:3 | n.1934_1936dupAAA | non_coding_transcript_exon | Exon 10 of 10 | ||||
| FH | ENST00000682162.1 | n.*1274_*1276dupAAA | non_coding_transcript_exon | Exon 11 of 11 | ENSP00000508203.1 |
Frequencies
GnomAD3 genomes 0.00103 AC: 157AN: 152166Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.00104 AC: 259AN: 249492 AF XY: 0.000992 show subpopulations
GnomAD4 exome AF: 0.00201 AC: 2933AN: 1461680Hom.: 8 Cov.: 31 AF XY: 0.00197 AC XY: 1430AN XY: 727144 show subpopulations
Age Distribution
GnomAD4 genome 0.00103 AC: 157AN: 152284Hom.: 0 Cov.: 31 AF XY: 0.000819 AC XY: 61AN XY: 74474 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Pathogenic:10Uncertain:4
FH: PM3:Strong, PS3:Moderate, PM2:Supporting, PM4:Supporting
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).
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 (PMID: 31444830, 33166576, 34994643); 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)
PM3, PM4
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, internal data). However, individuals who are homozygous for this variant do not have clinical features of FHD (gnomAD, internal data, 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, internal data). 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 gene product 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.
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.
Fumarase deficiency Pathogenic:5Uncertain:1Other:1
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 0.0019 in 1613964 control chromosomes in the gnomAD database (v4), including 8 homozygotes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in FH causing Fumarate Hydratase Deficiency phenotype (0.0011). 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 associated 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 that do not allow convincing conclusions about the variant effect due to lack of homozygous control activity measurements (example, Tregoning_2013, Loeffen_2005, Coughlin_1998). However, in at-least one of the ascertained studies, the most pronounced variant effect results in 1.9% of normal activity in an individual who harbored this variant in compound heterozygosity with a different loss of function (LOF) variant (Pollard_2005). The following publications have been ascertained in the context of this evaluation (PMID: 15987702, 22703879, 29909963, 24441663, 9635293, 16510303, 23612258, 16151915, 25985877, 27541980, 24182348, 16639410, 31444830, 32782288, 31794323, 34337822). ClinVar contains an entry for this variant (Variation ID: 42095). In summary, while this variant has been reported in the literature, the cancer risk of this variant remains uncertain for this highly variable phenotype that is known to have incomplete penetrance. Addtional large prospective studies are needed to fully ascertain the associated cancer risks for this variant. Based on the evidence outlined above, this variant is likely pathogenic for AR-Fumarase deficiency when observed in combination with other pathogenic/likely pathogenic variants in the FH gene.
Hereditary leiomyomatosis and renal cell cancer Pathogenic:3Uncertain:1
This variant is considered likely benign with respect to hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM ID: 150800). However it may predispose to fumarate hydratase (FH) deficiency (OMIM ID: 606812) when detected in trans with a pathogenic variant (compound heterozygous), but not when detected in the homozygous state. Functional studies have not interrogated the role of this variant in the absence of a second pathogenic variant, and therefore we consider its role in disease to be unclear.
Hereditary cancer-predisposing syndrome Pathogenic:1Benign:1
The c.1431_1433dupAAA (p.K477dup) alteration, located in coding exon 10 of the FH gene, results from an in-frame duplication of 3 nucleotides at positions 1431 to 1433. This results in the duplication of a lysine residue at codon 477. 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 available evidence, the FH c.1431_1433dupAAA (p.K477dup) alteration is classified as pathogenic in the compound heterozygous state for autosomal recessive FH deficiency; however, it is not considered a risk factor for HLRCC. Based on data from gnomAD, the c.1431_1433dupAAA allele has an overall frequency of 0.102% (285/280892) total alleles studied. The highest observed frequency was 0.512% (53/10360) of Ashkenazi Jewish alleles. 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 (Gellera, 1990; Rustin, 1997; Coughlin, 1998; Loeffen, 2005; Pollard, 2005; Deschauer, 2006; Ottolenghi, 2011; Ezgu, 2013; Tregoning, 2013). 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). 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 hereditary leiomyomatosis and renal cell cancer (HLRCC) including renal cancer, uterine leiomyomas and subcutaneous leiomyomas, although at least one of these individuals carried another FH alteration (phase unknown) (Chen, 2014; Martínek, 2015; Ylisaukko-oja, 2006; Ezgu, 2013). 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, 2020; Forde, 2020; Pahl, 2018; Ambry internal data). This amino acid position is well conserved in available vertebrate species. A cell line derived from a patient with FH deficiency, who is compound heterozygous for this alteration and FH p.R233H, showed defective energy and redox metabolism at the mRNA level (Raimundo, 2008). This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as pathogenic.
Fumarase deficiency;C1708350:Hereditary leiomyomatosis and renal cell cancer Pathogenic:1
FH-related disorder Pathogenic:1
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.
not specified Uncertain:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at