rs863223992

Positions:

• chr1-241500456-T-TGTGA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000143.4(FH):​c.1370_1371insTCAC​(p.Ala458HisfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T457T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FH NM_000143.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.66

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 18 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 28 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-241500456-T-TGTGA is Pathogenic according to our data. Variant chr1-241500456-T-TGTGA is described in ClinVar as [Pathogenic]. Clinvar id is 214405.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.1370_1371insTCAC	p.Ala458HisfsTer10	frameshift_variant	9/10	ENST00000366560.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FH	ENST00000366560.4	c.1370_1371insTCAC	p.Ala458HisfsTer10	frameshift_variant	9/10	1	NM_000143.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2016	The c.1370_1371insTCAC pathogenic variant in the FH gene causes a frameshift starting with codon Alanine 458, changes this amino acid to a Histidine residue and creates a premature Stop codon at position 10 of the new reading frame, denoted p.Ala458HisfsX10. This pathogenic variant is predicted to cause loss of normal protein function through protein truncation due to the last 53 amino acids being replaced by 9 aberrant amino acids. Although this pathogenic variant has not been previously reported to our knowledge, its presence is consistent with a diagnosis of hereditary leiomyomatosis and renal cell cancer (HLRCC). The variant is found in FH panel(s). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 09, 2023	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 214405). This premature translational stop signal has been observed in individual(s) with clinical features of FH-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala458Hisfs*10) in the FH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the FH protein. -

Fumarase deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 18, 2023

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2021

The c.1370_1371insTCAC pathogenic mutation, located in coding exon 9 of the FH gene, results from an insertion of 4 nucleotides at position 1370, causing a translational frameshift with a predicted alternate stop codon (p.A458Tfs*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 53 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 has been observed in at least one individual who has a personal or family history that is consistent with FH-associated disease (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs863223992; hg19: chr1-241663756;