Variant chr1-241504053-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The ENST00000366560.4(FH):c.1097G>A(p.Ser366Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,696 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S366S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FH
ENST00000366560.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.37

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000366560.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

PP5

Variant 1-241504053-C-T is Pathogenic according to our data. Variant chr1-241504053-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 214419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FH	NM_000143.4 linkuse as main transcript	c.1097G>A	p.Ser366Asn	missense_variant	7/10	ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4 linkuse as main transcript	c.1097G>A	p.Ser366Asn	missense_variant	7/10	1	NM_000143.4	ENSP00000355518	P1	P07954-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461696

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727136

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 366 of the FH protein (p.Ser366Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with multiple cutaneous and uterine leiomyomatosis (MCUL) or hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 12761039, 12772087, 16237213; Invitae). This variant is also known as G968A or S323N. ClinVar contains an entry for this variant (Variation ID: 214419). 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%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 20, 2023	PP3, PP4, PP5, PM1, PM2_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 26, 2023	The FH c.1097G>A (p.Ser366Asn) variant has been reported in the published literature in individuals with phenotypes associated with hereditary leiomyomatosis and renal cell cancer (HLRCC)(PMID: 12772087 (2003), 16237213 (2005), 21630274 (2011), 31299266 (2019)). Immunohistochemical analysis of tumors from patients with this variant showed loss of heterozygosity and were positive for (2-succinyl) cysteine (2SC) (termed protein succination) due to deficient fumarase (PMID: 21630274 (2011)). Additionally, this variant is predicted to alter the active site of the FH protein (PMID: 21445611 (2011), 12761039 (2003)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2024	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 FH c.968G>A, p.Ser323Asn; This variant is associated with the following publications: (PMID: 15937070, 12761039, 31299266, 18366737, 21630274, 12772087, 16597677, 16029320, 16237213, 30761759, 22561013, 35022142, 31831373, 21445611) -

Hereditary leiomyomatosis and renal cell cancer

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 03, 2022	The FH c.1097G>A (p.Ser366Asn) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been identified in multiple individuals with leiomyomas and/or renal cell carcinoma (PMID: 12761039, 12772087, 21630274). The tumors of at least three of these individuals also demonstrated loss of heterozygosity (PMID: 12761039, 21630274). In addition, immunohistochemical analysis of tumors from patients with this germline variant have shown an accumulation of succinated proteins as a result of fumarase deficiency (PMID: 21630274). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant is also known as p.Ser323Asn in the literature. In summary, this variant meets criteria to be classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 17, 2023	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12761039, 31299266, 31831373, 21630274, 12772087]. -

Fumarase deficiency

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 22, 2023

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The p.S366N pathogenic mutation (also known as c.1097G>A), located in coding exon 7 of the FH gene, results from a G to A substitution at nucleotide position 1097. The serine at codon 366 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in numerous individuals with multiple cutaneous and uterine leiyomyomatosis (Alam NA et al. J Mol Diagn. 2005 Oct;7:437-43; Toro JR et al. Am. J. Hum. Genet. 2003 Jul;73:95-106; Bardella C et al. J. Pathol. 2011 Sep;225(1):4-11; Gupta S et al. Hum Pathol, 2019 Sep;91:114-122; Ambry internal data). Immunohistochemical analysis of tumors in patients with the germline p.S366N mutation have shown that this alteration results in an accumulation of succinated proteins as a result of deficient fumarase; these patients' tumors also demonstrated loss of heterozygosity (Bardella C et al. J. Pathol. 2011 Sep;225(1):4-11). In addition, the p.S366N variant has been predicted to alter the enzymatic active site of the FH protein (Picaud S et al. J. Inherit. Metab. Dis. 2011 Jun;34:671-6; Alam NA et al. Hum. Mol. Genet. 2003 Jun;12:1241-52). Based on internal structural analysis, this variant is anticipated to disrupt a region of known function (Ajalla Aleixo MA et al. FEBS J. 2019 May;286:1925-1940; Mechaly AE et al. FEBS Lett. 2012 Jun;586:1606-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as S323N (c.968G>A) in some published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

5.1

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MutPred

0.70

Loss of phosphorylation at S366 (P = 0.0501);

MVP

0.98

MPC

0.90

ClinPred

1.0

GERP RS

5.7

Varity_R

0.98

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

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