rs587781682

chr1-241508644-G-Achr1-241508644-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_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. 13/21 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. 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.52

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]

ACMG classification

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, 11 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 [Likely_pathogenic]. Clinvar id is 826742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 id is 141355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241508644-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-241508644-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FH	NM_000143.4	c.697C>T	p.Arg233Cys	missense_variant	5/10	ENST00000366560.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FH	ENST00000366560.4	c.697C>T	p.Arg233Cys	missense_variant	5/10	1	NM_000143.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 32

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: 5 AN: 1461564 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	FH: PM1:Strong, PM2, PM5, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 19, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 10, 2023	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; Invitae). This variant is also known as c.568C>T, p.Arg190Cys. ClinVar contains an entry for this variant (Variation ID: 141355). 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. 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. -

Fumarase deficiency Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 13, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	May 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 30, 2023	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	5.1	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.89		Loss of catalytic residue at R233 (P = 0.0152);
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.97

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

LitVar

Other links and lift over

dbSNP: rs587781682; hg19: chr1-241671944; COSMIC: COSV100845036; COSMIC: COSV100845036;