NM_000143.4:c.1120C>A

Variant names:

• chr1-241502559-G-T
• rs876660446
• NM_000143.4:c.1120C>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_000143.4(FH):​c.1120C>A​(p.Pro374Thr) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P374P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FH NM_000143.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.35
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• hereditary leiomyomatosis and renal cell cancer

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• fumaric aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• pheochromocytoma-paraganglioma

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• leiomyosarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000143.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 132 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 1.2708 (below the threshold of 3.09). Trascript score misZ: 2.0634 (below the threshold of 3.09). GenCC associations: The gene is linked to fumaric aciduria, hereditary leiomyomatosis and renal cell cancer, hereditary pheochromocytoma-paraganglioma, leiomyosarcoma, pheochromocytoma-paraganglioma.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 1-241502559-G-T is Pathogenic according to our data. Variant chr1-241502559-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 233497.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4	c.1120C>A	p.Pro374Thr	missense_variant	Exon 8 of 10	ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.1120C>A	p.Pro374Thr	missense_variant	Exon 8 of 10	1	NM_000143.4	ENSP00000355518.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 19, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P374T variant (also known as c.1120C>A), located in coding exon 8 of the FH gene, results from a C to A substitution at nucleotide position 1120. The proline at codon 374 is replaced by threonine, an amino acid with highly similar properties. This variant was detected in a family whose clinical history is consistent with hereditary leiomyomatosis and renal cell cancer (HLRCC) (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant is anticipated to result in a decrease in function (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.99
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.1	H
PhyloP100		9.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.85		Loss of disorder (P = 0.0908);
MVP		0.99
MPC		1.0
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.95
gMVP		0.98
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs876660446; hg19: chr1-241665859;