NM_000143.4:c.988A>C

Variant names:

• chr1-241504162-T-G
• rs776313200
• NM_000143.4:c.988A>C
• FH p.Thr330Pro

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 16 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PP3_StrongPP5_Strong

The NM_000143.4(FH):c.988A>C (p.Thr330Pro) 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: 7.48). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV006586506: Functional studies indicate this variant impacts protein function [PMID:37255402].". 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.T330I: Uncertain_significance (ClinVar VariationId 1437249, 1 star); 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: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.48
• Publications: 3 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: Pathogenic. The variant received 16 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV006586506: Functional studies indicate this variant impacts protein function [PMID: 37255402].
	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.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

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.988A>C p.Thr330Pro	missense	Exon 7 of 10	Prot: NP_000134.2

FH NM_000143.4

MANE Select

HGVSc / HGVSpc.988A>Cp.Thr330Pro

Exon rankExon 7 of 10

missense

Prot: NP_000134.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FH ENST00000366560.4	TSL:1MANE Select	c.988A>C p.Thr330Pro	missense	Exon 7 of 10	Prot: ENSP00000355518.4 UniProt:
	FH ENST00000958409.1		c.985A>C p.Thr329Pro	missense	Exon 7 of 10	Prot: ENSP00000628468.1 UniProt:
	FH ENST00000932939.1		c.940A>C p.Thr314Pro	missense	Exon 7 of 10	Prot: ENSP00000602998.1 UniProt:

FH ENST00000366560.4

TSL:1MANE Select

HGVSc / HGVSpc.988A>Cp.Thr330Pro

Exon rankExon 7 of 10

missense

Prot: ENSP00000355518.4UniProt: P07954-1

FH ENST00000958409.1

HGVSc / HGVSpc.985A>Cp.Thr329Pro

Exon rankExon 7 of 10

missense

Prot: ENSP00000628468.1UniProt: A0ACI8UZJ7

FH ENST00000932939.1

HGVSc / HGVSpc.940A>Cp.Thr314Pro

Exon rankExon 7 of 10

missense

Prot: ENSP00000602998.1UniProt: 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

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary leiomyomatosis and renal cell cancer (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	0.93
GPN-Star LLR	N/A	-8.5
GPN-Star score	N/A	8.5
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.98	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Pathogenic	4.3	H
PhyloP100	Uncertain	7.5
popEVE	Benign	-4.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Varity_R	N/A	0.98
VESM-3B	Benign	-13

Showing 28 of 28 scores

Splicing Scores

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

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs776313200;

hg19: chr1-241667462;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar