rs201502246

Variant names:

• chr1-241504242-A-G
• rs201502246
• NM_000143.4:c.908T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PP2 PP3_Strong

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7
• Conservation: PhyloP100: 8.71
• Publications: 4 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, 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 24 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, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4	c.908T>C	p.Leu303Ser	missense_variant	Exon 7 of 10	ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.908T>C	p.Leu303Ser	missense_variant	Exon 7 of 10	1	NM_000143.4	ENSP00000355518.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152246 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 250126 AF XY: 0.00000739

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1461658 Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32 AN XY: 727124

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1111918

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74392

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:3

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). ClinVar contains an entry for this variant (Variation ID: 41584). 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: 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. -

Mar 04, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Nov 09, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2 -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary cancer-predisposing syndrome Uncertain:2

May 03, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 04, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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% (Internal data). The variant allele was found at a frequency of 4e-05 in 1613904 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FH causing Autosomal Recessive Fumarate Hydratase Deficiency (4e-05 vs 0.0011) or Autosomal Dominant Hereditary Leiomyomatosis And Renal Cell Cancer (2.5e-06), allowing no conclusion about variant significance. c.908T>C has been reported in the literature and at our laboratory in a compound heterozygous individual affected with fumarase deficiency (e.g. Kimonis_2012, internal testing) and an individual affected with a pheochromocytoma with a father affected with renal cell carcinoma (e.g. Richter_2019). 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) although cultured skin fibroblasts from an individual carrying this variant and another pathogenic variant p.Pro174Arg have 25% of WT fumarase activity (Kimonis_2012). 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 VUS-possibly pathogenic. -

Fumarase deficiency Uncertain:1

Aug 10, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		8.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.74		Loss of stability (P = 0.0343);
MVP		0.99
MPC		0.75
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.98
Mutation Taster		=1/99	disease causing

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

Other links and lift over

dbSNP: rs201502246; hg19: chr1-241667542;