rs752232718

Positions:

chr1-241508652-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.61

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:

FH (HGNC:):

FH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
FH	NM_000143.4 linkuse as main transcript	c.689A>G	p.Lys230Arg	missense_variant	5/10	ENST00000366560.4	NP_000134.2	P07954-1A0A0S2Z4C3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4 linkuse as main transcript	c.689A>G	p.Lys230Arg	missense_variant	5/10	1	NM_000143.4	ENSP00000355518.4		P07954-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251276

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135796

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727124

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:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
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. -

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

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.88

MutPred

0.65

Loss of methylation at K230 (P = 0.0377);

MVP

0.99

MPC

0.88

ClinPred

1.0

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

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