rs201502246

Positions:

chr1-241504242-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PP3_StrongBS2

The NM_000143.4(FH):c.908T>C(p.Leu303Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,904 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. L303F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

FH
NM_000143.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7

Conservation

PhyloP100: 8.71

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 2 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000143.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.962

BS2

High AC in GnomAdExome4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FH	NM_000143.4 linkuse as main transcript	c.908T>C	p.Leu303Ser	missense_variant	7/10	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.908T>C	p.Leu303Ser	missense_variant	7/10	1	NM_000143.4	ENSP00000355518.4		P07954-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

250126

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135404

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1461658

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

0.0000576

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:3

Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2024	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal history of pheochromocytoma whose tumor demonstrated loss of FH on immunohistochemistry testing and who also had a family history of renal cancer (PMID: 30050099); This variant is associated with the following publications: (PMID: 22595425, 22703879, 20549362, 30761759, 33052056, 35821608, 35993574, 36773955, 30050099) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 303 of the FH protein (p.Leu303Ser). This variant is present in population databases (rs201502246, gnomAD 0.002%). This missense change has been observed in individuals with autosomal recessive fumarase deficiency and/or paraganglioma-pheochromocytoma syndrome (PMID: 22595425, 35821608; Invitae). ClinVar contains an entry for this variant (Variation ID: 41584). 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: 22595425). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 09, 2022	PP3, PM2 -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	May 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 25, 2024	The p.L303S variant (also known as c.908T>C), located in coding exon 7 of the FH gene, results from a T to C substitution at nucleotide position 908. The leucine at codon 303 is replaced by serine, an amino acid with dissimilar properties. This alteration was identified, in trans with another FH missense alteration, in a 12-year-old girl with mild fumarase deficiency (Kimonis VE et al. Mol. Genet. Metab. 2012 Sep;107:241-2). This variant has also been reported in an individual with an adrenal pheochromocytoma whose tumor demonstrated loss of heterozygosity of FH; this individual's father also had a history of renal cell carcinoma (Richter S et al. Genet. Med. 2018 Jul). Based on internal structural analysis, L303S is more disruptive to the central domain than several nearby internally pathogenic variants (Ambry internal data; Ajalla Aleixo MA et al. FEBS J 2019 05;286(10):1925-1940). 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 dominant HLRCC is unclear. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 26, 2024

Variant summary: FH c.908T>C (p.Leu303Ser) results in a non-conservative amino acid change located in the Fumarate lyase, N-terminal domain (IPR022761) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250126 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.908T>C has been reported in the literature in a compound heterozygous individual affected with fumarase deficiency (e.g. Kimonis_2012) and an individual affected with a pheochromocytoma with a father affected with renal cell carcinoma (e.g. Richter_2019). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect on catalytic activity of this variant in vitro (e.g. Wilde_2023). The following publications have been ascertained in the context of this evaluation (PMID: 22595425, 30050099, 37255402). ClinVar contains an entry for this variant (Variation ID: 41584). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Fumarase deficiency

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.4

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.95

Sift

Uncertain

0.011

Sift4G

Uncertain

0.023

Polyphen

1.0

Vest4

0.87

MutPred

0.74

Loss of stability (P = 0.0343);

MVP

0.99

MPC

0.75

ClinPred

0.98

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.73

gMVP

0.98

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