rs1060500903

chr1-241500479-TC-T

Variant summary

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

The NM_000143.4(FH):c.1347del(p.Met449IlefsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FH NM_000143.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.48

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 31 pathogenic variants in the truncated region.
• PP5: Variant 1-241500479-TC-T is Pathogenic according to our data. Variant chr1-241500479-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 405924.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.1347del	p.Met449IlefsTer5	frameshift_variant	9/10	ENST00000366560.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FH	ENST00000366560.4	c.1347del	p.Met449IlefsTer5	frameshift_variant	9/10	1	NM_000143.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461784 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727186

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 02, 2016

This truncation removes the last 56 amino acids (Met454-Lys510) from the full-length FH protein. 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). In addition, another downstream truncation (p.Ala458Hisfs*10) that removes the last 53 amino acids of the FH protein has been classified as Likely Pathogenic at Invitae. This suggests that C-terminal truncation of FH is deleterious to protein function. This variant has been reported in the literature in an individual affected with multiple cutaneous and uterine leiomyomatosis (PMID: 11865300), and in a family with four affected members (PMID: 12761039). This variant is also known in the literature as 1-bp del. in codon 507. This sequence change deletes 1 nucleotide from exon 9 of the FH mRNA (c.1347delG), causing a frameshift at codon 449. This creates a premature translational stop signal in the previous to last exon of the FH mRNA (p.Met449Ilefs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 57 amino acids of the FH protein. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2023

The c.1347delG pathogenic mutation, located in coding exon 9 of the FH gene, results from a deletion of one nucleotide at nucleotide position 1347, causing a translational frameshift with a predicted alternate stop codon (p.M449Ifs*5). This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with FH-related disease (Ambry internal data; Alam, NA et al. Hum Mol Genet 2003 Jun;12(11):1241-52; Forde, C et al. Eur Urol Oncol 2020 Dec;3(6):764-772). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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)		0.0		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: rs1060500903; hg19: chr1-241663779;