rs398123163

Positions:

• chr1-241500533-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000143.4(FH):​c.1293del​(p.Glu432LysfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,638 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T431T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: FH NM_000143.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.179

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 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 43 pathogenic variants in the truncated region.
• PP5: Variant 1-241500533-CT-C is Pathogenic according to our data. Variant chr1-241500533-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 92452.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.1293del	p.Glu432LysfsTer17	frameshift_variant	9/10	ENST00000366560.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FH	ENST00000366560.4	c.1293del	p.Glu432LysfsTer17	frameshift_variant	9/10	1	NM_000143.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461638 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727116

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Glu432Lysfs*17) in the FH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the FH protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary leiomyomatosis and renal cell carcinoma (PMID: 12772087, 17392716). It has also been observed to segregate with disease in related individuals. This variant is also known as 1164delA and 1162delA. ClinVar contains an entry for this variant (Variation ID: 92452). This variant disrupts a region of the FH protein in which other variant(s) (p.Trp500*) have been determined to be pathogenic (PMID: 9635293, 20549362, 21398687). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 05, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2022	Frameshift variant predicted to result in protein truncation, as the last 79 amino acids are replaced with 16 different amino acids; Published functional studies demonstrate a damaging effect: decreased tetramer formation and catalytic efficiencies (Grocott 2019); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.1164delA; This variant is associated with the following publications: (PMID: 17392716, 21404119, 29423582, 28300276, 31746132, 12772087) -

Hereditary leiomyomatosis and renal cell cancer Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jan 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 06, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Fumarase deficiency Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 07, 2023	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2024

The c.1293delA pathogenic mutation, located in coding exon 9 of the FH gene, results from a deletion of one nucleotide at nucleotide position 1293, causing a translational frameshift with a predicted alternate stop codon (p.E432Kfs*17). This alteration, designated as 1164delA, was previously identified in an individual with papillary type II renal cell carcinoma diagnosed at age 17 and a family history of renal cell carcinoma and leiomyomas, consistent with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) (Refae MA et al. Nat Clin Pract Oncol. 2007 Apr;4:256-61). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs398123163; hg19: chr1-241663833;