NM_000143.4:c.1127A>C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PP2PP3_ModeratePP5

The NM_000143.4(FH):c.1127A>C(p.Gln376Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q376H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

FH
NM_000143.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:2B:1O:1

Conservation

PhyloP100: 2.56

Publications

11 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, 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

FH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_000143.4

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, 0.9

PP5

Variant 1-241502552-T-G is Pathogenic according to our data. Variant chr1-241502552-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42094.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4 link	c.1127A>C	p.Gln376Pro	missense_variant	Exon 8 of 10	ENST00000366560.4	NP_000134.2	P07954-1A0A0S2Z4C3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4 link	c.1127A>C	p.Gln376Pro	missense_variant	Exon 8 of 10	1	NM_000143.4	ENSP00000355518.4		P07954-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000636

AC:

AN:

251422

AF XY:

0.0000883

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000168

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000513

AC:

AN:

1111964

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68048

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000745

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:2Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 376 of the FH protein (p.Gln376Pro). This variant is present in population databases (rs200796606, gnomAD 0.01%). This missense change has been observed in individual(s) with fumarate hydratase deficiency (FHD) (PMID: 10896297, 15221078, 16876016, 28747166). It has also been observed to segregate with disease in related individuals. This variant is also known as 998A>C, Gln13Pro, and Gln333Pro. ClinVar contains an entry for this variant (Variation ID: 42094). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FH protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FH function (PMID: 17182618, 18313410). For these reasons, this variant has been classified as Pathogenic. -

Jan 27, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in either the homozygous state or in trans with another FH variant in individuals with fumarate hydratase (FH) deficiency referred for genetic testing at GeneDx and in the literature; however the parents and other heterozygous relatives of these individuals were not reported as having features of hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 10896297, 15221078, 16876016, 28747166); Studies suggest that in the heterozygous state, this variant is not associated with an increased risk to develop HLRCC-related tumors; however, there have been recent reports of this variant observed in individuals with history of renal cell carcinoma and/or pheochromocytomas (PMID: 18366737, 34994643, 34439371, 35971132, 35441217); Published functional studies demonstrate a damaging effect: the variant abolishes enzymatic activity and disrupts FH tetramerization (PMID: 37255402); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 998A>C, Gln333Pro, and Gln13Pro; This variant is associated with the following publications: (PMID: 19151755, 25637381, 21445611, 15221078, 17182618, 18313410, 20549362, 10896297, 28747166, 16155190, 20301679, 18366737, 35971132, 34439371, 35441217, 36612198, 34994643, 16876016, 36672771, 23210851, 37255402) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Apr 11, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fumarase deficiency

Pathogenic:2Benign:1Other:1

Mar 27, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Likely benign

Review Status:flagged submission

Collection Method:research

- -

Oct 05, 2017

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was identified as homozygous -

Fumarase deficiency;C1708350:Hereditary leiomyomatosis and renal cell cancer

Pathogenic:2

May 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 20, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The FH c.1127A>C (p.Gln376Pro) missense change has a maximum subpopulation frequency of 0.011% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function and a crystal structure study predicted this alteration affects protein interaction and structural integrity (PMID: 21445611). Functional studies have shown that this missense change affects FH function in the homozygous state (PMID: 18313410, 19151755). This variant has been identified in individuals with fumarase deficiency in the homozygous and compound heterozygous state (PMID: 10896297, 15221078, 16876016, 28747166). It has also been reported in individuals with features of HLRCC (PMID: 28747166, 35441217). This variant is also known as 998A>C, Gln13Pro, and Gln333Pro. Based on the available evidence, this variant is classified as a pathogenic mutation in association with fumarase deficiency when in the homozygous or compound heterozygous state; however, the clinical significance with respect to the cancer predisposition syndrome hereditary leiomyomatosis and renal cell cancer remains unclear. -

Hepatocellular carcinoma

Pathogenic:1

May 17, 2022

CZECANCA consortium

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:case-control

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Mar 24, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Q376P variant (also known as c.1127A>C), located in coding exon 8 of the FH gene, results from an A to C substitution at nucleotide position 1127. The glutamine at codon 376 is replaced by proline, an amino acid with similar properties. This alteration has been identified in a homozygous state or in conjunction with other FH alterations in individuals affected with autosomal recessive FH deficiency and was found to segregate with disease in siblings from these families (Remes AM et al. J. Mol. Med., 2004 Aug;82:550-4; Phillips TM et al. Pediatr. Neurol., 2006 Aug;35:150-3; Zeman J et al. J. Inherit. Metab. Dis., 2000 Jun;23:371-4; Chan MMY et al. BMC Med. Genet., 2017 07;18:79). In the cases where parents of these children who carried this alteration were ascertained for autosomal dominant HLRCC no evidence of uterine or dermal leiomyomas or renal manifestations were identified, despite half the normal fumarate hydratase activity in their blood mononuclear cells (Remes AM et al. J. Mol. Med., 2004 Aug;82:550-4; Chan MMY et al. BMC Med. Genet., 2017 07;18:79; Zeman J et al. J. Inherit. Metab. Dis., 2000 Jun;23:371-4). Cells derived from a homozygous patient showed other cellular anomalies including abnormal protein profiles, FH cellular localization, and cellular growth (Raimundo N et al. Biochim. Biophys. Acta, 2008 May;1782:287-94; Raimundo N et al. Oncogene, 2009 Mar;28:1261-73). This alteration lies withing a core helix and is predicted to affect subunit interactions and the structural integrity of the protein (Picaud S et al. J. Inherit. Metab. Dis., 2011 Jun;34:671-6; Ambry internal data). Of note, this alteration is also designated as c.998A>C in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is expected to be causative of autosomal recessive FH deficiency when present along with a second likely pathogenic/ pathogenic variant on the other allele; however, the clinical significance for autosomal dominiant HLRCC is unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.90

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

4.5

PhyloP100

2.6

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.59

MVP

0.99

MPC

1.1

ClinPred

1.0

GERP RS

6.0

Varity_R

0.99

gMVP

0.99

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over