1-241497861-C-T

Position:

• chr1-241497861-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000143.4(FH):​c.1500G>A​(p.Trp500Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FH NM_000143.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.75

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0215 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-241497861-C-T is Pathogenic according to our data. Variant chr1-241497861-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 265151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241497861-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FH	NM_000143.4	c.1500G>A	p.Trp500Ter	stop_gained	10/10	ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.1500G>A	p.Trp500Ter	stop_gained	10/10	1	NM_000143.4	ENSP00000355518	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary leiomyomatosis and renal cell cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jan 17, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 27, 2017

This variant is denoted FH c.1500G>A at the cDNA level and p.Trp500Ter (W500X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA), and is predicted to cause loss of normal protein function through protein truncation. Also published as FH c.1371G>A (p.Trp457X) using alternate nomenclature, this variant has been reported in a large family with HLRCC as well as in an individual with a single cutaneous leiomyoma (Gardie 2011, Buelow 2016). In addition, the adjacent nucleotide change resulting in the same nonsense variant c.1499G>A (p.W500X), reported as p.W458X using alternate nomenclature, was identified in the compound heterozygous state with another FH variant in a child with fumarate hydratase deficiency and significantly decreased FH enzyme activity (Coughlin 1998). Based on currently available evidence, we consider FH c.1500G>A to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 13, 2021

The p.W500* pathogenic variant (also known as c.1500G>A), located in coding exon 10 of the FH gene, results from a G to A substitution at nucleotide position 1500. This changes the amino acid from a tryptophan to a stop codon within coding exon 10. This alteration occurs at the 3' terminus of theFH gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 2%/10 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration disrupts normal FH folding and is anticipated to result in a significant decrease in structural stability (Ambry internal data). This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with FH-related disease and segregates with disease in one of these families (Ambry internal data; Gardie B et al. J. Med. Genet., 2011 Apr;48:226-34; Buelow B et al. Am. J. Surg. Pathol., 2016 07;40:982-8). This alteration is also referred to as p.Trp457X (c.1371G>A) in the literature. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D
Vest4		0.82
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs886039368; hg19: chr1-241661161;