rs121913121

chr1-241513661-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5 PP3_Strong PP5_Very_Strong

The NM_000143.4(FH):c.320A>C(p.Asn107Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,812 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N107K) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: FH NM_000143.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.46

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-241513660-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 2101618.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 1-241513661-T-G is Pathogenic according to our data. Variant chr1-241513661-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FH	NM_000143.4	c.320A>C	p.Asn107Thr	missense_variant	3/10	ENST00000366560.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FH	ENST00000366560.4	c.320A>C	p.Asn107Thr	missense_variant	3/10	1	NM_000143.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727206

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: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2023	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 N64T; This variant is associated with the following publications: (PMID: 16029320, 26900816, 21445611, 23211287, 21630274, 16757530, 19939761, 15937070, 12761039, 29909963, 11865300, 34604083, 36777509, 24625422) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 26, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FH function (PMID: 11865300). 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: 92455). This variant is also known as c.191A>C, p.Asn64Thr. This missense change has been observed in individuals with hereditary leiomyomatosis and renal cell cancer (PMID: 11865300, 15937070, 16757530, 21630274, 23211287, 24625422, 26900816). 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 asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 107 of the FH protein (p.Asn107Thr). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 17, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 12, 2015	- -

Hereditary leiomyomatosis and renal cell cancer Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2006	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 05, 2023	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12761039, 16237213, 11865300, 31831373, 34604083]. Functional studies indicate this variant impacts protein function [PMID: 16237213,11865300, 16597677, 20109171]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jan 17, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Dec 17, 2021	- -
Likely pathogenic, criteria provided, single submitter	research	Academic Department of Medical Genetics, University of Cambridge	Jan 26, 2018	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 05, 2022	The p.N107T pathogenic mutation (also known as c.320A>C), located in coding exon 3 of the FH gene, results from an A to C substitution at nucleotide position 320. The asparagine at codon 107 is replaced by threonine, an amino acid with similar properties. This alteration, designated as Asn64Thr or N64T, was identified in at least 12 apparently unrelated individuals from the UK who had multiple leiomyomata; in one of these families, the alteration segregated with disease in 16 affected relatives (Tomlinson I et al. Nat Genet. 2002 Apr;30(4):406-10; Alam N et al. Hum Mol Genet. 2003 Jun 1;12(11):1241-52). This alteration has been reported in additional individuals with cutaneous and/or uterine leiomyomas and/or renal cell carcinoma, some of whose tumors had loss of FH on immunohistochemical staining or FH loss-of-heterozygosity (Sanz-Ortega J et al. Am J Surg Pathol. 2013 Jan;37(1):74-80; Carvajal-Carmona L et al. J Clin Endocrinol Metab. 2006 Aug;91(8):3071-5; Wei M et al. J Med Genet. 2006 Jan;43(1):18-27; Udager AM et al. Am. J. Surg. Pathol. 2014 Apr;38:567-77; Trpkov K et al. Am. J. Surg. Pathol. 2016 Jul;40:865-75; Bardella C et al. J. Pathol. 2011 Sep;225:4-11). In addition, this alteration is predicted to be deleterious by in silico analysis. 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	0.93
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	5.0	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.76		Gain of catalytic residue at N107 (P = 0.0349);
MVP		0.99
MPC		0.85
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.97

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

Other links and lift over

dbSNP: rs121913121; hg19: chr1-241676961;