1-241497841-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_ModeratePP5_Moderate

The NM_000143.4(FH):​c.1520T>A​(p.Leu507Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,456,946 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. L507P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FH
NM_000143.4 missense

Scores

16
2
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.05
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-241497841-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 501651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.896
PP5
Variant 1-241497841-A-T is Pathogenic according to our data. Variant chr1-241497841-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2842821.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FHNM_000143.4 linkc.1520T>A p.Leu507Gln missense_variant 10/10 ENST00000366560.4 NP_000134.2 P07954-1A0A0S2Z4C3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FHENST00000366560.4 linkc.1520T>A p.Leu507Gln missense_variant 10/101 NM_000143.4 ENSP00000355518.4 P07954-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000407
AC:
1
AN:
245416
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
132682
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000558
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1456946
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
724580
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 04, 2023In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu507 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12761039; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with FH-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 507 of the FH protein (p.Leu507Gln). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.68
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.33
D
MetaRNN
Pathogenic
0.90
D
MetaSVM
Pathogenic
0.95
D
MutationAssessor
Pathogenic
3.8
H
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-5.3
D
REVEL
Pathogenic
0.86
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.78
MutPred
0.51
Gain of disorder (P = 0.0412);
MVP
0.96
MPC
0.98
ClinPred
0.99
D
GERP RS
6.0
Varity_R
0.97
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.

Other links and lift over

dbSNP: rs1425094515; hg19: chr1-241661141; API