rs1553340708

chr1-241500575-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000143.4(FH):c.1251_1252insA(p.His418ThrfsTer34) variant causes a frameshift change involving the alteration of a non-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. L417L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: FH NM_000143.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0430

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 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 56 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-241500575-G-GT is Pathogenic according to our data. Variant chr1-241500575-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 460337.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FH	NM_000143.4	c.1251_1252insA	p.His418ThrfsTer34	frameshift_variant	9/10	ENST00000366560.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FH	ENST00000366560.4	c.1251_1252insA	p.His418ThrfsTer34	frameshift_variant	9/10	1	NM_000143.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 23, 2018

For these reasons, this variant has been classified as Pathogenic. In addition, a missense substitution at codon 419 (p.Ser419Pro) has been determined to be likely pathogenic (PMID: 16597677, 15937070). This suggests that the serine residue, which is disrupted by this frameshift variant, is critical for FH protein function and that other substitutions at this position may also be pathogenic. This variant disrupts the last 92 amino acid residues (His418-Lys510) of the full-length FH protein. While this particular variant has not been reported in the literature, a downstream truncating variant (p.Trp500*) deleting the last 11 amino acids has been observed in an individual with fumarate hydratase deficiency (PMID: 9635293, 20549362). It was also shown to segregate with disease in a large family with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 21398687). This suggests that C-terminal truncation of FH is deleterious to protein function and may be pathogenic. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the FH gene (p.His418Thrfs*34). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 92 amino acid residues of the FH protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1553340708; hg19: chr1-241663875;