rs587781682

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000143.4(FH):c.697C>T(p.Arg233Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 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. R233G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

FH
NM_000143.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.52

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

hereditary leiomyomatosis and renal cell cancer
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
fumaric aciduria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
pheochromocytoma-paraganglioma
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
leiomyosarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 26 uncertain in NM_000143.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-241508644-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 826742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 132 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 1.2708 (below the threshold of 3.09). Trascript score misZ: 2.0634 (below the threshold of 3.09). GenCC associations: The gene is linked to fumaric aciduria, hereditary leiomyomatosis and renal cell cancer, hereditary pheochromocytoma-paraganglioma, leiomyosarcoma, pheochromocytoma-paraganglioma.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 1-241508644-G-A is Pathogenic according to our data. Variant chr1-241508644-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 141355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4 link	c.697C>T	p.Arg233Cys	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.697C>T	p.Arg233Cys	missense_variant	Exon 5 of 10	1	NM_000143.4	ENSP00000355518.4		P07954-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461564

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111762

Other (OTH)

AF:

0.0000166

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Dec 18, 2024

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 cysteine, which is neutral and slightly polar, at codon 233 of the FH protein (p.Arg233Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary leiomyomatosis and renal cell cancer and fumarate hydratase deficiency (PMID: 2314594, 9300800, 15761418, 15937070, 21398687; internal data). This variant is also known as c.568C>T, p.Arg190Cys. ClinVar contains an entry for this variant (Variation ID: 141355). 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: 2314594, 9300800, 21398687, 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: 11865300, 12772087, 15937070, 17960613, 20618355, 22127509). 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. -

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FH: PM1:Strong, PM2, PM5, PP3, PS3:Supporting -

Jul 09, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The FH c.697C>T (p.Arg233Cys) variant has been reported in the published literature in individuals and families with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMIDs: 36777509 (2023), 33167498 (2020), 21398687 (2011), 15937070 (2006), 15761418 (2005)) and fumarate hydratase deficiency (PMIDs: 32999401 (2020), 2314594 (1990)). Functional studies report this variant results in decreased enzyme activity and impaired protein function (PMID: 21398687 (2011), 16597677 (2006), 2314594 (1990)). The frequency of this variant in the general population, 0.0000066 (1/152132 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Feb 01, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in trans or phase unknown with FH Lys477dup (also known as Lys434ins) in children with fumarase deficiency (Gellera 1990, Chakravorty 2020); Not observed at 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 p.Arg190Cys; This variant is associated with the following publications: (PMID: 16639410, 28300276, 21445611, 11865300, 16597677, 9300800, 18366737, 15761418, 20618355, 12612654, 21404119, 2314594, 15937070, 28152038, 32999401, 21398687) -

Feb 19, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fumarase deficiency

Pathogenic:3

Nov 04, 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.697C>T (p.Arg233Cys) results in a non-conservative amino acid change located in the Class II fumarases domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251278 control chromosomes. c.697C>T has been reported in the literature in multiple individuals affected with Fumarate Hydratase Deficiency or Hereditary Leiomyomatosis And Renal Cell Cancer. These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.698G>A, p.Arg233His), supporting the critical relevance of codon 233 to FH protein function. The following publications have been ascertained in the context of this evaluation (PMID: 21398687, 9300800). ClinVar contains an entry for this variant (Variation ID: 141355). Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 17, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

May 27, 2021

Sema4, Sema4

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

May 30, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R233C pathogenic mutation (also known as c.697C>T), located in coding exon 5 of the FH gene, results from a C to T substitution at nucleotide position 697. The arginine at codon 233 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation, which occurs in the enzyme active site, has been identified in multiple families with HLRCC to date (Picaud S et al. J. Inherit. Metab. Dis. 2011 Jun;34(3):671-6; Gardie B et al. J. Med. Genet. 2011 Apr;48(4):226-34), including a family where the mutation was found to segregate with renal cell carcinoma through two generations (Wei MH et al. J. Med. Genet. 2006 Jan;43(1):18-27). This mutation has also been observed in a family with multiple cutaneous and uterine leiomyomata (Chuang GS et al. J. Am. Acad. Dermatol. 2005 Mar;52(3 Pt 1):410-6). In addition, this mutation was observed in a compound heterozygous state with a second pathogenic mutation in a child with fumarase deficiency (Rustin P et al. Biochim. Biophys. Acta. 1997 Aug 22;1361(2):185-97). Of note, this alteration is also designated as R190C (568C>T) in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation. -

Hereditary leiomyomatosis and renal cell cancer

Pathogenic:1

Apr 04, 2025

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: 33167498, 37230921, 21398687, 35715365, 37580017, 31831373, 2314594, 32999401]. Functional studies indicate this variant impacts protein function [PMID: 35216667]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

5.1

PhyloP100

9.5

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.8

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MutPred

0.89

Loss of catalytic residue at R233 (P = 0.0152);

MVP

0.97

MPC

1.2

ClinPred

1.0

GERP RS

5.7

Varity_R

0.98

gMVP

0.97

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over