NM_000143.4:c.989C>T

Variant names:

• chr1-241504161-G-A
• rs200028270
• NM_000143.4:c.989C>T
• FH p.Thr330Ile

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+8 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 8 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5PP3_Moderate

The NM_000143.4(FH):c.989C>T (p.Thr330Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.35). Variant has been reported in ClinVar as Uncertain Significance (★). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.T330P: Pathogenic/Likely_pathogenic (ClinVar VariationId 575043, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T330A: Uncertain_significance (ClinVar VariationId 847461, 2 stars); p.T330S: Uncertain_significance (ClinVar VariationId 460384, 1 star); p.T330= (synonymous): Likely_benign (ClinVar VariationId 1561277, 2 stars); p.T330= (synonymous): Benign/Likely_benign (ClinVar VariationId 3230468, 2 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: FH NM_000143.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.35
• Publications: 0 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, Natera, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Genomics England PanelApp
• fumaric aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Natera
• 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 12 pathogenic, 1 benign (OR vs. background: 41.7).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00191) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.T330P: Pathogenic/Likely_pathogenic (ClinVar VariationId 575043, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.T330A: Uncertain_significance (ClinVar VariationId 847461, 2 stars); p.T330S: Uncertain_significance (ClinVar VariationId 460384, 1 star); p.T330= (synonymous): Likely_benign (ClinVar VariationId 1561277, 2 stars); p.T330= (synonymous): Benign/Likely_benign (ClinVar VariationId 3230468, 2 stars)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000143.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FH	NM_000143.4	MANE Select	c.989C>T	p.Thr330Ile	missense	Exon 7 of 10	NP_000134.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FH	ENST00000366560.4	TSL:1 MANE Select	c.989C>T	p.Thr330Ile	missense	Exon 7 of 10	ENSP00000355518.4	P07954-1
	FH	ENST00000958409.1		c.986C>T	p.Thr329Ile	missense	Exon 7 of 10	ENSP00000628468.1	A0ACI8UZJ7
	FH	ENST00000932939.1		c.941C>T	p.Thr314Ile	missense	Exon 7 of 10	ENSP00000602998.1	A0ACI8TNT4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	12948	0.0000431	1	23218

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	24
AlphaMissense	Benign	-	0.29
BayesDel_addAF	Pathogenic	D	0.56
BayesDel_noAF	Pathogenic	-	0.57
CADD	Pathogenic	-	28
DANN	Pathogenic	-	1.0
DEOGEN2	Pathogenic	D	0.91
Eigen	Pathogenic	-	0.99
Eigen_PC	Pathogenic	-	0.95
FATHMM_MKL	Pathogenic	D	0.99
FuncVEP CTI	Benign	-	0.22
GPN-Star LLR	N/A	-	-7.4
GPN-Star score	N/A	-	7.4
LIST_S2	Pathogenic	D	0.99
M_CAP	Pathogenic	D	0.82
MetaRNN	Pathogenic	D	0.93
MetaSVM	Pathogenic	D	1.0
Mutation Taster	N/A	disease causing	7/93
MutationAssessor	Pathogenic	M	3.0
PhyloP100	Pathogenic	-	9.3
popEVE	Benign	-	-3.4
PrimateAI	Pathogenic	D	0.81
PROVEAN	Uncertain	D	-3.4
REVEL	Pathogenic	-	0.92
Sift	Pathogenic	D	0.0
Sift4G	Uncertain	D	0.0020
Varity_R	N/A	-	0.84
VESM-3B	Benign	-	-7.5

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.0
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs200028270;

hg19: chr1-241667461;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar