Variant rs398123168 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000143.4(FH):c.952C>T(p.His318Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FH
NM_000143.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 9.35

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

PP5

Variant 1-241504198-G-A is Pathogenic according to our data. Variant chr1-241504198-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241504198-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-241504198-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FH	NM_000143.4 linkuse as main transcript	c.952C>T	p.His318Tyr	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.952C>T	p.His318Tyr	missense_variant	7/10	1	NM_000143.4	ENSP00000355518	P1	P07954-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727228

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

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	May 19, 2023	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 92458). This variant is also known as 823C>T or H275Y. This missense change has been observed in individual(s) with hereditary leiomyomatosis and renal cell cancer (HLRCC) or multiple cutaneous and uterine leiomyoma (MCUL) (PMID: 12772087, 14632190, 20618355). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 318 of the FH protein (p.His318Tyr). -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 22, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2021	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as His275Tyr; This variant is associated with the following publications: (PMID: 16237213, 21445611, 14632190, 12772087, 15761418, 26113603, 20618355, 28400895, 21398687, 16510303, 28300276, 27635946, 16597677, 29456767) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Hereditary leiomyomatosis and renal cell cancer

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jan 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 05, 2023	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12772087, 14632190, 20618355, 28400895]. Functional studies indicate this variant impacts protein function [PMID: 29456767]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 23, 2021	- -

Fumarase deficiency;C1708350:Hereditary leiomyomatosis and renal cell cancer

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 12, 2021

- -

Fumarase deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 16, 2023

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2023

The p.H318Y pathogenic mutation (also known as c.952C>T), located in coding exon 7 of the FH gene, results from a C to T substitution at nucleotide position 952. The histidine at codon 318 is replaced by tyrosine, an amino acid with similar properties. This alteration has been reported in multiple individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome, and has been shown to segregate with disease in at least two unrelated families (Toro JR et al. Am. J. Hum. Genet., 2003 Jul;73:95-106; Martinez-Mir A et al. J. Invest. Dermatol., 2003 Oct;121:741-4; Pithukpakorn M et al. J. Med. Genet., 2006 Sep;43:755-62; Smit DL et al. Clin. Genet., 2011 Jan;79:49-59; Aissani B et al. Endocr. Relat. Cancer, 2015 Aug;22:633-43; Sommer LL et al. J Dermatol Case Rep, 2016 Nov;10:53-55; Muller M et al. Clin. Genet., 2017 Dec;92:606-615). In addition, biochemical analyses indicate that this alteration is defective for enzymatic activity and oligomerization (Bulku A et al. Open Biochem J, 2018 Jan;12:1-15). Of note, this alteration is also reported as c.823C>T, p.H275Y in the literature. 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). 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

0.87

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.2

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.2

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.85

MutPred

0.75

Gain of phosphorylation at H318 (P = 0.111);

MVP

0.97

MPC

1.0

ClinPred

1.0

GERP RS

5.7

Varity_R

0.96

gMVP

0.96

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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