rs786202833

Positions:

• chr1-241512118-T-C
• chr1-241512118-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000143.4(FH):​c.404A>G​(p.His135Arg) variant causes a missense change involving the alteration of a 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FH NM_000143.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.20

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 1-241512118-T-C is Pathogenic according to our data. Variant chr1-241512118-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FH	NM_000143.4	c.404A>G	p.His135Arg	missense_variant	4/10	ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.404A>G	p.His135Arg	missense_variant	4/10	1	NM_000143.4	ENSP00000355518	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2024	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 c.275A>G, p.His92Arg; This variant is associated with the following publications: (PMID: 21445611, 15761418, 15663510, 21398687, 30741757, 31831373, 31524643, 31917494) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2023	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 135 of the FH protein (p.His135Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary leiomyomatosis and renal cell cancer (PMID: 15761418, 30741757; Invitae). ClinVar contains an entry for this variant (Variation ID: 186284). 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%. For these reasons, this variant has been classified as Pathogenic. -

Hereditary leiomyomatosis and renal cell cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jul 05, 2023

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 31524643, 30741757, 31831373, 15761418]. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 20, 2023

The p.H135R variant (also known as c.404A>G), located in coding exon 4 of the FH gene, results from an A to G substitution at nucleotide position 404. The histidine at codon 135 is replaced by arginine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals who have a personal or family history that is consistent with FH-associated disease (Ambry internal data; Personal Communication; Chuang GS et al. J. Am. Acad. Dermatol. 2005 Mar;52:410-6; Rabban JT et al. Am J Surg Pathol. 2019 05;43:639-655; Lau HD et al. Am J Surg Pathol. 2020 01;44:98-110). Of note, this variant may be referred to as p.H92R in some literature. 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.62		Loss of ubiquitination at K131 (P = 0.052);
MVP		0.96
MPC		1.0
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.97
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs786202833; hg19: chr1-241675418;