rs752232718

chr1-241508652-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_000143.4(FH):c.689A>G(p.Lys230Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. K230E) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: FH NM_000143.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.61

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 14 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000143.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-241508653-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 214375.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 1-241508652-T-C is Pathogenic according to our data. Variant chr1-241508652-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 429176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241508652-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FH	NM_000143.4	c.689A>G	p.Lys230Arg	missense_variant	5/10	ENST00000366560.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FH	ENST00000366560.4	c.689A>G	p.Lys230Arg	missense_variant	5/10	1	NM_000143.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251276 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135796

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461626 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727124

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: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 19, 2023	The FH c.689A>G (p.Lys230Arg) variant has been reported in the published literature in a newborn with Fumarase deficiency (PMID: 9635293 (1998)) and in individuals with conditions associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 11865300 (2002), 12761039 (2003), 12772087 (2003), 26900816 (2016), 26574848 (2016), 34604083 (2021)). Published functional studies showed reduced fumarase activity (PMID: 9635293 (1998), 11865300 (2002), 16206287 (2006), 19470762 (2009)). The frequency of this variant in the general population, 0.000004 (1/251276 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 230 of the FH protein (p.Lys230Arg). This variant is present in population databases (rs752232718, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant FH-related conditions and multiple cutaneous leiomyomas, uterine leiomyomas and/or renal cell carcinoma (PMID: 9635293, 11865300, 12761039, 12772087, 26574848, 31831373; Invitae). This variant is also known as Lys187Arg. ClinVar contains an entry for this variant (Variation ID: 429176). 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: 9635293, 11865300, 16206287, 19470762). For these reasons, this variant has been classified as Pathogenic. -

Fumarase deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 10, 2022

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 20, 2022

The p.K230R pathogenic mutation (also known as c.689A>G), located in coding exon 5 of the FH gene, results from an A to G substitution at nucleotide position 689. The lysine at codon 230 is replaced by arginine, an amino acid with highly similar properties. This alteration, also designated as K187R, was detected in a newborn with fumarase deficiency in the homozygous state (Coughlin EM et al. Mol. Genet. Metab. 1998 Apr; 63(4):254-62) and in the heterozygote state in multiple individuals with features consistent with a diagnosis of HLRCC (Tomlinson IP et al. Nat. Genet. 2002 Apr; 30(4):406-10; Alam NR et al. Hum. Mol. Genet. 2003 Jun;12(11):1241-52; Toro JR et al. Am. J. Hum. Genet. 2003 Jul;73(1):95-106; Trpkov K et al. Am J Surg Pathol. 2016 07;40:865-75; Al-Shinnag M et al. Front Oncol. 2021 Sep;11:738822; Ambry internal data). In addition, this alteration has been shown to have a significant impact on fumarate hydratase enzymatic activity (Coughlin EM et al. Mol. Genet. Metab. 1998 Apr; 63(4):254-62; Tomlinson IP et al. Nat. Genet. 2002 Apr; 30(4):406-10). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.65		Loss of methylation at K230 (P = 0.0377);
MVP		0.99
MPC		0.88
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.93

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: rs752232718; hg19: chr1-241671952;