NM_000143.4:c.560C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000143.4(FH):​c.560C>T​(p.Ser187Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S187P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FH
NM_000143.4 missense

Scores

17
1
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3U:1

Conservation

PhyloP100: 9.60

Publications

5 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1
In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_000143.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-241508782-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 3230452.Status of the report is criteria_provided_single_submitter, 1 stars.
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, 0.961
PP5
Variant 1-241508781-G-A is Pathogenic according to our data. Variant chr1-241508781-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 393567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241508781-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 393567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241508781-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 393567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241508781-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 393567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241508781-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 393567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241508781-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 393567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241508781-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 393567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241508781-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 393567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241508781-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 393567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241508781-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 393567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241508781-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 393567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241508781-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 393567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241508781-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 393567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241508781-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 393567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241508781-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 393567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FHNM_000143.4 linkc.560C>T p.Ser187Leu missense_variant Exon 5 of 10 ENST00000366560.4 NP_000134.2 P07954-1A0A0S2Z4C3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FHENST00000366560.4 linkc.560C>T p.Ser187Leu missense_variant Exon 5 of 10 1 NM_000143.4 ENSP00000355518.4 P07954-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000399
AC:
1
AN:
250648
AF XY:
0.00
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 FIN exome
AF:
0.0000463
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460914
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726766
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33438
American (AMR)
AF:
0.00
AC:
0
AN:
44644
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26108
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39670
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86116
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53390
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5760
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111438
Other (OTH)
AF:
0.00
AC:
0
AN:
60350
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Apr 15, 2024
GeneDx
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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; This variant is associated with the following publications: (PMID: 26173633, 21445611, 37255402, 12772087, 36777509) -

Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 187 of the FH protein (p.Ser187Leu). This variant is present in population databases (rs398123166, gnomAD 0.004%). This missense change has been observed in individual(s) with hereditary leiomyomatosis and renal cell cancer (PMID: 12772087; internal data). This variant is also known as C431T and S144L. ClinVar contains an entry for this variant (Variation ID: 393567). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1
Aug 06, 2024
Ambry Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.S187L variant (also known as c.560C>T), located in coding exon 5 of the FH gene, results from a C to T substitution at nucleotide position 560. The serine at codon 187 is replaced by leucine, an amino acid with dissimilar properties. This alteration was previously identified to co-segregate with disease in one family with hereditary leiomyomatosis and renal cell cancer (HLRCC) and was absent in 210 unaffected controls (Toro JR et al. Am. J. Hum. Genet. 2003 Jul; 73(1):95-106). This variant has been observed in at least one individual with a personal and/or family history that is consistent with HLRCC (Ambry internal data). Based on structural analysis, this variant is anticipated to result in a loss of fumarate binding and catalysis (Ambry internal data; Picaud S et al. J. Inherit. Metab. Dis. 2011 Jun; 34(3):671-6; Mechaly AE et al. FEBS Lett. 2012 Jun; 586(11):1606-11). 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 likely to be pathogenic. -

Hereditary leiomyomatosis and renal cell cancer Uncertain:1
Jan 17, 2017
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance:Uncertain significance
Review Status:flagged submission
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.59
D
BayesDel_noAF
Pathogenic
0.61
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
1.0
D
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Pathogenic
0.79
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Pathogenic
4.7
H
PhyloP100
9.6
PrimateAI
Uncertain
0.79
T
PROVEAN
Pathogenic
-5.8
D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.97
MutPred
0.68
Loss of disorder (P = 0.0227);
MVP
0.98
MPC
0.92
ClinPred
0.99
D
GERP RS
6.0
Varity_R
0.99
gMVP
0.95
Mutation Taster
=5/95
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs398123166; hg19: chr1-241672081; API