rs750447792

Positions:

• chr1-241502522-T-C
• chr1-241502522-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000143.4(FH):​c.1157A>G​(p.Gln386Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q386E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FH NM_000143.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.01

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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000143.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-241502521-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1468692.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant 1-241502522-T-C is Pathogenic according to our data. Variant chr1-241502522-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 405939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241502522-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FH	NM_000143.4	c.1157A>G	p.Gln386Arg	missense_variant	8/10	ENST00000366560.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FH	ENST00000366560.4	c.1157A>G	p.Gln386Arg	missense_variant	8/10	1	NM_000143.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary leiomyomatosis and renal cell cancer Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 17, 2024	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 33789101, 31524643, 25292446, 21398687, 28300276]. Functional studies indicate this variant impacts protein function [PMID: 21398687, 25292446, 27097334]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The p.Gln386Arg (historically referred to as Gln343Arg) variant in FH has been reported in at least 3 individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC) and segregated with disease in >5 relatives (Gardie 2011 PubMed: 21398687; Muller 2017 PubMed: 28300276). It was also observed in ClinVar (Variation ID 405939) but absent in gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Studies on patient blood samples or derived cell lines demonstrate reduced FH activity (Gardie 2011 PubMed: 21398687; Muller 2017,PubMed: 28300276). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HLRCC. ACMG/AMP Criteria applied: PS4_Moderate, PP1_Moderate, PM2_Supporting, PP3, PP4. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 13, 2022	ClinVar contains an entry for this variant (Variation ID: 405939). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FH function (PMID: 21398687). 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. This variant is also known as c.1028A>G (p.Gln343Arg). This missense change has been observed in individual(s) with a personal and family history of hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 21398687, 25292446). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 386 of the FH protein (p.Gln386Arg). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2021	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.Gln343Arg; This variant is associated with the following publications: (PMID: 31524643, 21398687, 27097334, 28300276, 27161211, 29655270, 25292446) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2024

The p.Q386R pathogenic mutation (also known as c.1157A>G), located in coding exon 8 of the FH gene, results from an A to G substitution at nucleotide position 1157. The glutamine at codon 386 is replaced by arginine, an amino acid with highly similar properties. This alteration has been detected in multiple individuals and families with HLRCC-associated features, several with loss of FH staining by immunohistochemistry (IHC) in associated tissues (Gardie B et al. J Med Genet, 2011 Apr;48:226-34; Llamas-Velasco M et al. J Cutan Pathol, 2014 Nov;41:859-65; Muller M et al. Clin Genet, 2017 Dec;92:606-615; Lau HD et al. Am J Surg Pathol, 2020 01;44:98-110; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.76
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.054	T
Polyphen		0.68	P
Vest4		0.68
MutPred		0.60		Gain of methylation at Q386 (P = 0.0243);
MVP		0.98
MPC		0.97
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.87
gMVP		0.98

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

Other links and lift over

dbSNP: rs750447792; hg19: chr1-241665822;