Submissions for variant NM_000143.4(FH):c.698G>A (p.Arg233His)

gnomAD frequency: 0.00003  dbSNP: rs121913123

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000196988	SCV000230854	pathogenic	not provided	2018-04-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000196988	SCV000251419	pathogenic	not provided	2022-05-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: impaired fumarase activity (Lorenzato et al., 2008); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.569G>A, p.(R190H); This variant is associated with the following publications: (PMID: 23211287, 24117336, 21445611, 18176756, 21733559, 22127509, 15937070, 20618355, 16151915, 15761418, 11865300, 18313410, 12772087, 12761039, 27635946, 27051714, 26380143, 28300276, 28592388, 28748451, 28171700, 28628081, 27382802, 29984275, 34570182, 17960613, 15987702, 16237213, 16597677, 33447692, 32612247, 33167498, 29456767)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196988	SCV000283675	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 233 of the FH protein (p.Arg233His). This variant is present in population databases (rs121913123, gnomAD 0.004%). This missense change has been observed in individuals with hereditary leiomyomatosis and renal cell cancer (PMID: 11865300, 12772087, 15937070, 20618355, 22127509). This variant is also known as c.569G>A, p.Arg190His. ClinVar contains an entry for this variant (Variation ID: 16236). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FH protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FH function (PMID: 11865300, 17960613, 18313410, 21445611). This variant disrupts the p.Arg233 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21445611). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000017623	SCV000537239	pathogenic	Hereditary leiomyomatosis and renal cell cancer	2017-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000493379	SCV000581639	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-06	criteria provided, single submitter	clinical testing	The p.R233H pathogenic mutation (also known as c.698G>A), located in coding exon 5 of the FH gene, results from a G to A substitution at nucleotide position 698. This mutation has been identified in many patients and families affected with histologically confirmed cutaneous leiomyomata, uterine leiomyomata and renal tumors (Huter E et al. Acta Derm. Venereol. 2008;88(1):63-5; Smit DL et al. Clin. Genet. 2011 Jan;79(1):49-59; Wang C et al. JAAD Case Rep. 2015 May;1(3):150-2). This mutation has been demonstrated to result in decreased FH enzyme activity in multiple individuals (Tomlinson IP et al. Nat. Genet. 2002 Apr;30(4):406-10; Alam N et al. Hum. Mol. Genet. 2003 Jun;12(11):1241-52). In addition, this mutation was also detected in two unrelated individuals with demonstrated loss of heterozygosity for FH on tumor analysis (Gatalica Z et al. Hum. Pathol. 2011 Dec;42(12):1979-88; Sanz-Ortega J et al. Am. J. Surg. Pathol. 2013 Jan;37(1):74-80). Furthermore, data suggests that this mutation may represent a founder effect or occur at a mutation hotspot (Toro JR et al. Am. J. Hum. Genet. 2003 Jul;73(1):95-106; Wei M et al. J. Med. Genet. 2006 Jan;43(1):18-27). Of note, this alteration is also often referred to as p.R190H in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000196988	SCV001473885	pathogenic	not provided	2020-01-20	criteria provided, single submitter	clinical testing	The FH c.698G>A; p.Arg233His variant (rs121913123), also known as Arg190His for legacy nomenclature, is reported in the literature in numerous individuals affected with hereditary leiomyomatosis and renal cell cancer (Gatalica 2011, Kakar 2014, Picaud 2011, Raymond 2012, Sanz-Ortega 2013, Tomlinson 2002, Toro 2003), and shown to co-segregate with disease in a family (Toro 2003). This variant is also reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 16236). It is found in the general population with a low overall allele frequency of 0.002% (5/282680 alleles) in the Genome Aggregation Database. The arginine at codon 233 is highly conserved and is considered a mutational hotspot located in the active site of the fumarate hydratase enzyme (Picaud 2011). Computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious, and functional analyses show that this variant causes decreased enzymatic activity (Tomlinson 2002). Based on available information, this variant is considered to be pathogenic. REFERENCES Gatalica Z et al. Renal medullary carcinomas: histopathologic phenotype associated with diverse genotypes. Hum Pathol. 2011 Dec;42(12):1979-88. Kakar R et al. Multiple linear leiomyomas of the forehead as the presenting sign of Reed syndrome. Int J Dermatol. 2014 Mar;53(3):316-8. Picaud S et al. Structural basis of fumarate hydratase deficiency. J Inherit Metab Dis. 2011 Jun;34(3):671-6. Raymond VM et al. Familial renal cancer as an indicator of hereditary leiomyomatosis and renal cell cancer syndrome. Fam Cancer. 2012 Mar;11(1):115-21. Sanz-Ortega J et al. Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome. Am J Surg Pathol. 2013 Jan;37(1):74-80. Tomlinson IP et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002 Apr;30(4):406-10. Toro JR et al. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet. 2003 Jul;73(1):95-106.
Revvity Omics, Revvity	RCV000196988	SCV002022976	pathogenic	not provided	2021-12-27	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000196988	SCV002051726	pathogenic	not provided	2021-01-28	criteria provided, single submitter	clinical testing	PS3, PP3, PM1, PM2, PM3
MGZ Medical Genetics Center	RCV000017623	SCV002579506	pathogenic	Hereditary leiomyomatosis and renal cell cancer	2021-08-24	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV003128387	SCV003804876	pathogenic	See cases	2022-10-18	criteria provided, single submitter	clinical testing	ACMG categories: PS5,PM2,PM7,PP3,PP5
CeGaT Center for Human Genetics Tuebingen	RCV000196988	SCV004042475	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	FH: PS3, PM1, PM5, PP3, PS4:Supporting
Myriad Genetics, Inc.	RCV000017623	SCV004187875	pathogenic	Hereditary leiomyomatosis and renal cell cancer	2023-07-05	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16237213, 33167498, 31831373, 12772087, 15937070, 16151915, 15987702]. Functional studies indicate this variant impacts protein function [PMID: 26237645, 22677546, 17960613, 29456767]. This variant is expected to disrupt protein structure (internal Myriad data).
Baylor Genetics	RCV000178717	SCV004197346	pathogenic	Fumarase deficiency	2024-03-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000196988	SCV004218895	pathogenic	not provided	2021-09-30	criteria provided, single submitter	clinical testing	The FH c.698G>A (p.Arg233His, also known as Arg190His) variant has been reported in the published literature in individuals with renal cancer and HLRCC (PMIDs: 22127509 (2012), 21733559 (2011), 20618355 (2011), 18176756 (2008), 15937070 (2006)), and to segregate with disease in one family (PMID: 12772087 (2003)). In addition, experimental studies have shown this variant has deleterious effects on FH protein function (PMIDs: 18313410 (2008), 17960613 (2008), 11865300 (2002)). The frequency of this variant in the general population, 0.000039 (5/129044 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000017623	SCV005039358	pathogenic	Hereditary leiomyomatosis and renal cell cancer	2024-03-13	criteria provided, single submitter	clinical testing	Variant summary: FH c.698G>A (p.Arg233His) results in a non-conservative amino acid change located in the Fumarate lyase, N-terminal of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251278 control chromosomes. c.698G>A has been reported in the literature in multiple individuals affected with Hereditary Leiomyomatosis And Renal Cell Cancer and Fumarate Hydratase Deficiency and is reported as one of the most common pathogenic variants (examples: Toro_2003, Tomlinson_2002). Experimental evidence has shown this variant to affect protein function (example: Lorenzato_007). Other variants have been reported at this position, suggesting this codon may be a hotspot (p.R233C, p.R233L). The following publications have been ascertained in the context of this evaluation (PMID: 12772087, 11865300, 17960613). ClinVar contains an entry for this variant (Variation ID: 16236). Based on the evidence outlined above, the variant was classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004541007	SCV005040788	pathogenic	Spinocerebellar ataxia 45	2024-03-13	criteria provided, single submitter	clinical testing	Variant summary: FAT2 c.698G>A (p.Gly233Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 250934 control chromosomes (gnomAD). To our knowledge, no occurrence of c.698G>A in individuals affected with Spinocerebellar Ataxia 45 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000196988	SCV005197933	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
OMIM	RCV000017623	SCV000037898	pathogenic	Hereditary leiomyomatosis and renal cell cancer	2006-01-01	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000017623	SCV000606910	not provided	Hereditary leiomyomatosis and renal cell cancer		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV000178717	SCV001457346	pathogenic	Fumarase deficiency	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000196988	SCV001959128	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000196988	SCV001964751	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003330393	SCV004037575	not provided	Fumarase deficiency; Hereditary leiomyomatosis and renal cell cancer		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 03-05-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.