chr1-241504161-G-C

Variant names:

Variant summary

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

The NM_000143.4(FH):c.989C>G (p.Thr330Ser) 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.T330I: Uncertain_significance (ClinVar VariationId 1437249, 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.35

Publications

0 publications found

Variant links:

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

FH links:

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new If you want to explore the variant's impact on the transcript NM_000143.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 points.

PM1

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).

PM2

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.

PM5

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.T330= (synonymous): Likely_benign (ClinVar VariationId 1561277, 2 stars); p.T330= (synonymous): Benign/Likely_benign (ClinVar VariationId 3230468, 2 stars)

PP3

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>G	p.Thr330Ser	missense	Exon 7 of 10	NP_000134.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FH	ENST00000366560.4	TSL:1 MANE Select	c.989C>G	p.Thr330Ser	missense	Exon 7 of 10	ENSP00000355518.4	P07954-1
FH	ENST00000958409.1		c.986C>G	p.Thr329Ser	missense	Exon 7 of 10	ENSP00000628468.1	A0ACI8UZJ7
FH	ENST00000932939.1		c.941C>G	p.Thr314Ser	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					32
GnomAD4 exome					32
GnomAD4 genome					32

Showing 3 sources

Case/control cohorts

Cohort	Cases			Controls
Cohort	AF	AC	AN	AF	AC	AN
Epi25 (Epilepsy)	0.00	0	41958	0.0000150	1	66888

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

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	23
AlphaMissense	Benign	-	0.19
BayesDel_addAF	Pathogenic	D	0.41
BayesDel_noAF	Pathogenic	-	0.35
CADD	Pathogenic	-	27
DANN	Uncertain	-	1.0
DEOGEN2	Pathogenic	D	0.94
Eigen	Uncertain	-	0.49
Eigen_PC	Uncertain	-	0.60
FATHMM_MKL	Pathogenic	D	0.99
FuncVEP CTI	Benign	-	0.14
GPN-Star LLR	N/A	-	-6.2
GPN-Star score	N/A	-	6.2
LIST_S2	Pathogenic	D	0.97
M_CAP	Pathogenic	D	0.47
MetaRNN	Pathogenic	D	0.88
MetaSVM	Pathogenic	D	1.1
Mutation Taster	N/A	disease causing	27/73
MutationAssessor	Benign	M	2.0
PhyloP100	Pathogenic	-	9.3
popEVE	Benign	-	-3.1
PrimateAI	Uncertain	T	0.73
PROVEAN	Uncertain	D	-3.4
REVEL	Pathogenic	-	0.78
Sift	Benign	D	0.038
Sift4G	Benign	T	0.082
Varity_R	N/A	-	0.63
VESM-3B	Benign	-	-5.1

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Case/control cohorts

ClinVar

Computational Scores

Splicing Scores

Publications

Other links and lift over