chr1-241511968-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000143.4(FH):c.554A>G(p.Gln185Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. Q185H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FH
NM_000143.4 missense, splice_region

Scores

Splicing: ADA: 0.9997

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.26

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 18 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000143.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-241511968-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 574229.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant 1-241511968-T-C is Pathogenic according to our data. Variant chr1-241511968-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 214433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241511968-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4 link	c.554A>G	p.Gln185Arg	missense_variant, splice_region_variant	Exon 4 of 10	ENST00000366560.4	NP_000134.2	P07954-1A0A0S2Z4C3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4 link	c.554A>G	p.Gln185Arg	missense_variant, splice_region_variant	Exon 4 of 10	1	NM_000143.4	ENSP00000355518.4		P07954-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461548

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727066

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.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 03, 2024	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 185 of the FH protein (p.Gln185Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with leiomyomas (PMID: 11865300, 28300276; internal data). This variant is also known as p.Gln142Arg. ClinVar contains an entry for this variant (Variation ID: 214433). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects FH function (PMID: 11865300, 16237213, 21445611). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2017	The Q185R variant in the FH gene has previously been published in association with hereditary leiomyomatosis and renal cell cancer (Tomlinson et al., 2002; Alam et al., 2005; Muller et al., 2017). Alam et al. (2005) reported decreased FH enzyme activity of 46.1% in a heterozygous individual harboring the Q185R variant. This variant is not observed in large population cohorts (Lek et al., 2016). The Q185R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and is located within the enzyme active site (Picaud et al., 2011). In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on currently available evidence, the Q185R variant is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded. -

Hereditary leiomyomatosis and renal cell cancer

Pathogenic:1

Likely 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:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2024

The p.Q185R pathogenic mutation (also known as c.554A>G), located in coding exon 4 of the FH gene, results from an A to G substitution at nucleotide position 554. The glutamine at codon 185 is replaced by arginine, an amino acid with highly similar properties. This alteration been observed in multiple individuals who have a personal and/or family history that is consistent with FH-associated disease (Ambry internal data; Muller M et al. Clin. Genet. 2017 Dec;92:606-615; Tomlinson IP et al. Nat. Genet. 2002 Apr; 30(4):406-10). Based on internal structural assessment, this alteration destabilizes the structure of the N-terminal lobe (Ajalla Aleixo MA et al. FEBS J. 2019 May;286:1925-1940). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. 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

0.98

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

5.0

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MutPred

0.76

Loss of methylation at K183 (P = 0.0646);

MVP

0.97

MPC

1.0

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.10

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