1-241504160-AG-TA

Variant names:

• chr1-241504160-AG-TA
• NM_000143.4:c.989_990delCTinsTA
• FH p.Thr330Ile

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5

The NM_000143.4(FH):c.989_990delCTinsTA (p.Thr330Ile) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.35). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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.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: Not reported in ClinVar
• 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 6 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.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)

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.989_990delCTinsTA p.Thr330Ile	missense	N/A	Prot: NP_000134.2

FH NM_000143.4

MANE Select

HGVSc / HGVSpc.989_990delCTinsTAp.Thr330Ile

Exon rankN/A

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.989_990delCTinsTA p.Thr330Ile	missense	N/A	Prot: ENSP00000355518.4 UniProt:
	FH ENST00000958409.1		c.986_987delCTinsTA p.Thr329Ile	missense	N/A	Prot: ENSP00000628468.1 UniProt:
	FH ENST00000932939.1		c.941_942delCTinsTA p.Thr314Ile	missense	N/A	Prot: ENSP00000602998.1 UniProt:

FH ENST00000366560.4

TSL:1MANE Select

HGVSc / HGVSpc.989_990delCTinsTAp.Thr330Ile

Exon rankN/A

missense

Prot: ENSP00000355518.4UniProt: P07954-1

FH ENST00000958409.1

HGVSc / HGVSpc.986_987delCTinsTAp.Thr329Ile

Exon rankN/A

missense

Prot: ENSP00000628468.1UniProt: A0ACI8UZJ7

FH ENST00000932939.1

HGVSc / HGVSpc.941_942delCTinsTAp.Thr314Ile

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.3

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr1-241667460;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar