chr1-241504130-A-T

Position:

chr1-241504130-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000143.4(FH):c.1020T>A(p.Asn340Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,820 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. N340N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

FH
NM_000143.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 0.550

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:

FH (HGNC:):

FH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000143.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 1-241504130-A-T is Pathogenic according to our data. Variant chr1-241504130-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92447.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.1020T>A	p.Asn340Lys	missense_variant	7/10	ENST00000366560.4	NP_000134.2	P07954-1A0A0S2Z4C3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4 linkuse as main transcript	c.1020T>A	p.Asn340Lys	missense_variant	7/10	1	NM_000143.4	ENSP00000355518.4		P07954-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251316

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135824

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727216

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:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2021	Not observed at a significant frequency in large population cohorts (Lek 2016); 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: 24684806, 21398687, 12772087, 23757202, 18366737, 28748451, 19939761, 28171700, 21445611, 24441663, 16597677, 26457356, 15937070, 31162287, 30741757) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 19, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 340 of the FH protein (p.Asn340Lys). This variant is present in population databases (rs398123159, gnomAD 0.003%). This missense change has been observed in individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 12772087, 15937070, 26457356; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as 891T>A (N297K, N297D). ClinVar contains an entry for this variant (Variation ID: 92447). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 30, 2022	The FH c.1020T>A (p.Asn340Lys) variant (also known as 891T>A, N297K or N297D) has been reported in individuals with uterine fibroid/tumor (PMID: 30741757 (2019)) and HLRCC (PMIDs: 24441663 (2014), 16597677 (2006), 15937070 (2006), 12772087 (2003)). A cell line study indicated the variant caused significantly reduced FH enzyme activity in vitro (PMID: 16597677 (2006)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function also yielded predictions that this variant is damaging. The frequency of this variant in the general population, 0.000012 (3/251316 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. -

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	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 06, 2023	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 31831373, 31162287, 24441663, 15937070]. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2023	Variant summary: FH c.1020T>A (p.Asn340Lys) results in a non-conservative amino acid change located in the N-terminal Fumarate lyase domain (IPR022761) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251316 control chromosomes. c.1020T>A has been reported in the literature in multiple individuals affected with Hereditary Leiomyomatosis And Renal Cell Cancer (example, Kamihara_2021, Truong_2021, Forde_2020, Joseph_2015, Wei_FH_JMG_2006, Toro_FH_AJHG_2003). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31831373, 26457356, 34994643, 12772087, 34654685, 15937070). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Fumarase deficiency;C1708350:Hereditary leiomyomatosis and renal cell cancer

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 11, 2024

- -

Fumarase deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 02, 2024

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2023

The p.N340K variant (also known as c.1020T>A), located in coding exon 7 of the FH gene, results from a T to A substitution at nucleotide position 1020. The asparagine at codon 340 is replaced by lysine, an amino acid with similar properties. This alteration, referred to as N297K or N297D in some literature, has been detected in multiple HLRCC families (Ambry internal data; Wei MH et al. J Med Genet. 2006 Jan;43(1):18-27; Toro JR et al. Am J Hum Genet. 2003 Jul;73(1):95-106; Picaud S et al. J Inherit Metab Dis. 2011 Jun;34(3):671-6). This alteration has also been reported as a pathogenic mutation in a 24 year old woman from a cohort of 2060 women with uterine smooth muscle tumors (Rabban JT et al. Am J Surg Pathol, 2019 05;43:639-655). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Further, based on internal structural analysis, this variant is anticipated to result in a decrease in protein function (Ambry Internal Data; Picaud S et al. J Inherit Metab Dis. 2011 Jun;34(3):671-6). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

FH-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 12, 2023

The FH c.1020T>A variant is predicted to result in the amino acid substitution p.Asn340Lys. This variant has previously been reported to be causative for hereditary leiomyomatosis and renal cell cancer in several individuals (Toro et al. 2003. PubMed ID: 12772087, HGMD/ClinVar listed as T891A; Wei et al. 2006. PubMed ID: 15937070, reported as c.891T>A (N297K); Joseph et al. 2015. PubMed ID: 26457356, reported as c.1020T>A, p.N340K; Rabban JT et al 2019. PubMed ID: 30741757). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-241667430-A-T) and is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/92447/?new_evidence=true). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

1.0

MutPred

0.83

Gain of MoRF binding (P = 0.0281);

MVP

0.98

MPC

1.1

ClinPred

1.0

GERP RS

3.4

Varity_R

0.95

gMVP

0.99

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

Other links and lift over