chr1-241502552-T-G

Position:

chr1-241502552-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PP3_ModeratePP5BS2

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

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 links:

FH (HGNC:):

FH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000143.4

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 id is 42094.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, not_provided=1, Pathogenic=5, Likely_pathogenic=1}.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FH	NM_000143.4 linkuse as main transcript	c.1127A>C	p.Gln376Pro	missense_variant	8/10	ENST00000366560.4	NP_000134.2	P07954-1A0A0S2Z4C3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4 linkuse as main transcript	c.1127A>C	p.Gln376Pro	missense_variant	8/10	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

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251422

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135880

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000168

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000971

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

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2025	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Uncertain significance, flagged submission	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Fumarase deficiency

Pathogenic:2Benign:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, flagged submission	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 05, 2017	This variant was identified as homozygous -

Fumarase deficiency;C1708350:Hereditary leiomyomatosis and renal cell cancer

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 07, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Apr 20, 2023	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

Likely pathogenic, no assertion criteria provided

case-control

CZECANCA consortium

May 17, 2022

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over