rs121913121

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5PP3_StrongPP5_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

Scores

14
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.46
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank MANE Protein UniProt
FHNM_000143.4 linkc.320A>C p.Asn107Thr missense_variant Exon 3 of 10 ENST00000366560.4 NP_000134.2 P07954-1A0A0S2Z4C3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FHENST00000366560.4 linkc.320A>C p.Asn107Thr missense_variant Exon 3 of 10 1 NM_000143.4 ENSP00000355518.4 P07954-1

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
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:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:4
Aug 18, 2023
GeneDx
Significance: 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; 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) -

Dec 25, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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 also known as c.191A>C, p.Asn64Thr. ClinVar contains an entry for this variant (Variation ID: 92455). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FH function (PMID: 11865300). For these reasons, this variant has been classified as Pathogenic. -

Oct 12, 2015
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 17, 2019
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary leiomyomatosis and renal cell cancer Pathogenic:3
Jul 05, 2023
Myriad Genetics, Inc.
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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]. -

Aug 01, 2006
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jan 17, 2017
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:3
Dec 17, 2021
Sema4, Sema4
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Oct 05, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jan 26, 2018
Academic Department of Medical Genetics, University of Cambridge
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

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. -

Fumarase deficiency;C1708350:Hereditary leiomyomatosis and renal cell cancer Pathogenic:1
Apr 03, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Fumarase deficiency Pathogenic:1
Jan 31, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: FH c.320A>C (p.Asn107Thr) results in a non-conservative amino acid change located in the Fumarase/aspartase N-terminal domain (Fumarase/aspartase (N-terminal domain)) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251456 control chromosomes. c.320A>C has been reported in the literature in multiple individuals affected with Autosomal dominant Leiomyomatosis and renal cell cancer (Tomlinson_2002, Carvajal-Carmona_2006, Wei_2006, Sanz-Ortega_2013, Udager_2014, Scharnitz_2023). 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: 16757530, 23211287, 36777509, 11865300, 26900816, 24625422, 15937070). ClinVar contains an entry for this variant (Variation ID: 92455). Based on the evidence outlined above, the variant was classified as pathogenic. -

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
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121913121; hg19: chr1-241676961; API