rs863224007

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_000143.4(FH):c.1189G>A(p.Gly397Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,636 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 Likely pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

FH
NM_000143.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.38

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 12 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000143.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.905

PP5

Variant 1-241502490-C-T is Pathogenic according to our data. Variant chr1-241502490-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 214422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241502490-C-T is described in Lovd as [Pathogenic]. Variant chr1-241502490-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FH	NM_000143.4 linkuse as main transcript	c.1189G>A	p.Gly397Arg	missense_variant	8/10	ENST00000366560.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FH	ENST00000366560.4 linkuse as main transcript	c.1189G>A	p.Gly397Arg	missense_variant	8/10	1	NM_000143.4	P1	P07954-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152144

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

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251386

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135850

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461492

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727046

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:

0.00000810

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

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:

0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 30, 2023	The frequency of this variant in the general population, 0.000004 (1/251386 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in multiple unrelated individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 12761039 (2003), 24441663 (2014), 21630274 (2011), 21398687 (2011), 31636096 (2020), 19967458 (2010), 201618355 (2011), 19183173 (2009)) and papillary renal cell cancers (pRCC) (PMID: 25790038 (2015), 26900816 (2016)). Functional assays found reduced fumarase activity (PMID: 12761039 (2003), 21398687 (2011)). This pathogenic variant is also known as p.G354R (c.1060G>A) in the literature. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2023	Observed in the heterozygous state in multiple unrelated patients with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) and tumor studies consistent with pathogenic variants in this gene (Alam et al., 2003; Badeloe et al., 2009; Alrashdi et al., 2010; Smit et al., 2011; Kovac et al., 2015; Trpkov et al., 2016; Chan et al., 2019; Pivovarcikova et al., 2019; Casey et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.1060G>A, p.(Gly354Arg); This variant is associated with the following publications: (PMID: 20618355, 19183174, 25790038, 19967458, 28748451, 31162287, 26900816, 31636096, 31842557, 21398687, 33938658, 21445611, 12761039, 35971132, 34189567) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 397 of the FH protein (p.Gly397Arg). This variant is present in population databases (no rsID available, gnomAD no frequency). This missense change has been observed in individual(s) with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 12761039, 19967458, 20618355, 21398687). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1060G>A (p.Gly354Arg). ClinVar contains an entry for this variant (Variation ID: 214422). 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: 21398687). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary leiomyomatosis and renal cell cancer

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jan 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 09, 2021	- -
Pathogenic, no assertion criteria provided	research	Department of Traditional Chinese Medicine, Fujian Provincial Hospital	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 06, 2023	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19967458, 20618355, 12761039, 16237213, 21398687, 31831373, 24441663]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Fumarase deficiency

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 10, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.82; 3Cnet: 0.99). Functional studies provide evidence of the variant reducing the FH enzymatic activity by ~50% in peripheral blood lymphocytes (PMID: 21398687) Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence for an allelic disorder, autosomal dominant Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) (OMIM: 150800) (ClinVar ID: VCV000214422). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 2021

The p.G397R pathogenic mutation (also known as c.1189G>A), located in coding exon 8 of the FH gene, results from a G to A substitution at nucleotide position 1189. The glycine at codon 397 is replaced by arginine, an amino acid with dissimilar properties. This pathogenic mutation has been reported in numerous individuals diagnosed with HLRCC or the MCUL (multiple cutaneous and uterine leiomymata) phenotype (Alam NA et al. Hum. Mol. Genet. 2003 Jun;12:1241-52; Badeloe S et al. Br. J. Dermatol. 2009 Mar;160:707-9; Alrashdi I et al. Fam. Cancer. 2010 Jun;9:239-43; Smit DL et al. Clin. Genet. 2011 Jan;79:49-59; Bardella C et al. J Pathol, 2011 Sep;225:4-11; Chen YB et al. Am J Surg Pathol, 2014 May;38:627-37; Trpkov K et al. Am J Surg Pathol, 2016 07;40:865-75; Casey RT et al. Clin Cancer Res, 2020 01;26:391-396). In one study, roughly 50% of FH enzymatic activity in peripheral blood lymphocytes was seen in two out of four French HLRCC patients who carry this FH mutation (Gardie B et al. J. Med. Genet. 2011 Apr;48:226-34). In addition, the p.G397R alteration is predicted to destabilize the local structure and protein-protein interactions of the FH protein (internal Ambry structural data). Of note, this pathogenic mutation is also known as p.G354R (c.1060G>A) in the 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.6

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.023

Polyphen

0.98

Vest4

1.0

MutPred

0.56

Gain of methylation at G397 (P = 0.0124);

MVP

0.98

MPC

0.69

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.99

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