rs398123166

Variant names:

• chr1-241508781-G-A
• rs398123166
• NM_000143.4:c.560C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-241508781-G-A
• chr1-241508781-G-C
• chr1-241508781-G-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 9.60
• Publications: 5 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: 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
FH	NM_000143.4	c.560C>T	p.Ser187Leu	missense_variant	Exon 5 of 10	ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.560C>T	p.Ser187Leu	missense_variant	Exon 5 of 10	1	NM_000143.4	ENSP00000355518.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250648 AF XY: 0.00

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

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

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

Other links and lift over

dbSNP: rs398123166; hg19: chr1-241672081;