rs863223965

Positions:

• chr1-241508757-A-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.584T>C​(p.Met195Thr) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M195V) has been classified 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:5 O:1
• Conservation: PhyloP100: 8.95

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 0 benign, 14 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 chr1-241508758-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 460368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 1-241508757-A-G is Pathogenic according to our data. Variant chr1-241508757-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 214373.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.584T>C	p.Met195Thr	missense_variant	5/10	ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.584T>C	p.Met195Thr	missense_variant	5/10	1	NM_000143.4	ENSP00000355518.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary leiomyomatosis and renal cell cancer Pathogenic:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 05-23-2016 by Lab Memorial Sloan-Kettering Department of Pathology. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 21, 2023	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22764886, 30171332, 32154112, 12772087]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 16, 2022	Variant summary: FH c.584T>C (p.Met195Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251158 control chromosomes. c.584T>C has been reported in the literature in multiple individuals affected with cutaneous leiomyomas, sporadic uterine fibroids, uterine leiomyoma and renal cell cancer, including an affected mother and son (e.g. Toro_2003, Kubinova_2013, Cunha_2018, Yonamine_2020, Zhang_2020). These data indicate that the variant is very likely to be associated with Hereditary Leiomyomatosis And Renal Cell Cancer. Additionally, a variant affecting the same codon has been reported in association with Leiomyomatosis and renal cell cancer (p.Met195Val). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 195 of the FH protein (p.Met195Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with uterine fibroids and hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 12772087, 22764886; Invitae). This variant is also known as 455T>C (M152T). ClinVar contains an entry for this variant (Variation ID: 214373). 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: 22764886). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 16029320, 21445611, 22473397, 12772087, 22764886, 16237213, 30171332, 29978187, 31444830, 28873162) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2024

The p.M195T variant (also known as c.584T>C), located in coding exon 5 of the FH gene, results from a T to C substitution at nucleotide position 584. The methionine at codon 195 is replaced by threonine, an amino acid with similar properties. This alteration has been observed in multiple individuals who have a personal and/or family history that is consistent with FH-associated disease (Ambry internal data; Kubinova K et al. J. Obstet. Gynaecol. Res., 2013 Jan;39:410-4; Tolvanen J et al. Hum. Reprod., 2012 Jun;27:1865-9; Yonamine T et al. Urol Case Rep, 2020 May;30:101141; Toro JR et al. Am. J. Hum. Genet., 2003 Jul;73:95-106; Carlo MI et al. JAMA Oncol, 2018 09;4:1228-1235). Another variant at the same codon, p.M195V (c.583A>G), has been observed in individuals with a personal and/or family history that is consistent with FH-associated disease (Ambry internal data; Tolvanen J et al. Hum Reprod, 2012 Jun;27:1865-9). 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 variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.31	B
Vest4		0.96
MutPred		0.66		Loss of stability (P = 0.0772);
MVP		0.98
MPC		1.0
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.90

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: rs863223965; hg19: chr1-241672057;