1-241508643-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000143.4(FH):c.698G>A(p.Arg233His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R233C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

FH
NM_000143.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:22O:2

Conservation

PhyloP100: 7.50

Variant links:

Genes affected

FH (HGNC:3700): (fumarate hydratase) The protein encoded by this gene is an enzymatic component of the tricarboxylic acid (TCA) cycle, or Krebs cycle, and catalyzes the formation of L-malate from fumarate. It exists in both a cytosolic form and an N-terminal extended form, differing only in the translation start site used. The N-terminal extended form is targeted to the mitochondrion, where the removal of the extension generates the same form as in the cytoplasm. It is similar to some thermostable class II fumarases and functions as a homotetramer. Mutations in this gene can cause fumarase deficiency and lead to progressive encephalopathy. [provided by RefSeq, Jul 2008]

FH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000143.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-241508644-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 141355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

PP5

Variant 1-241508643-C-T is Pathogenic according to our data. Variant chr1-241508643-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241508643-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4 link	c.698G>A	p.Arg233His	missense_variant	Exon 5 of 10	ENST00000366560.4	NP_000134.2	P07954-1A0A0S2Z4C3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4 link	c.698G>A	p.Arg233His	missense_variant	Exon 5 of 10	1	NM_000143.4	ENSP00000355518.4		P07954-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251278

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000647

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:11

Apr 25, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 28, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PP3, PM1, PM2, PM3 -

May 05, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FH: PS3, PM1, PM5, PP3, PS4:Supporting -

Dec 27, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Jan 20, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 30, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary leiomyomatosis and renal cell cancer

Pathogenic:5Other:1

Jul 05, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

Jan 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 17, 2017

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: 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. -

Mar 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Aug 24, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fumarase deficiency

Pathogenic:2

Mar 13, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Dec 10, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_supporting, PS3_Moderate, PM2_Supporting, PP1_Strong, PP3_Moderate, PP4_Strong c.698G>A, located in exon 5 of the FH gene, is predicted to result in the substitution of arginine by histidine at codon 233, p.(Arg233His). This variant is found in 2/268142 with an allele frequency of 0.0007% in the gnomAD v2.1.1 database (non-cancer data set). (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score for this variant (0.963) suggests a deleterious effect on protein function according to Pejaver 2022 thresholds (PMID: 36413997)(PP3_Moderate). Experimental studies measuring enzyme activity have shown this variant has deleterious effects on FH protein function (PMID: 11865300, PMID: 18313410, PMID: 17960613)(PS3_Moderate). In addition, FH c.698G>A has been identified in several patients from different independent families cosegregating with clinical features of hereditary leiomyomatosis (HLRCC) (PMID: 12772087, PMID: 15937070, PMID: 11865300, PMID: 16151915 and internal data)(PP4_Strong, PP1_Strong). Also, this variant has been reported in an individual (1 year old) with another pathogenic variant in trans diagnosed with FH deficiency and maternity and paternity are confirmed (PMID: 16151915)(PM3_supporting). This variant has been reported in the ClinVar database (21x Pathogenic) and in the LOVD database (5x pathogenic, 5x uncertain significance). Based on currently available information, the variant c.698G>A is classified as a pathogenic variant according to ACMG guidelines. -

Jan 17, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. The arginine at codon 233 is replaced by histidine, an amino acid with highly similar properties. 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. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as a pathogenic mutation. -

See cases

Pathogenic:1

Oct 18, 2022

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS5,PM2,PM7,PP3,PP5 -

Spinocerebellar ataxia 45

Pathogenic:1

Mar 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Fumarase deficiency;C1708350:Hereditary leiomyomatosis and renal cell cancer

Other:1

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

5.1

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MVP

0.99

MPC

1.1

ClinPred

1.0

GERP RS

5.7

Varity_R

0.97

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over