rs1031919395

Variant names:

• chr1-241519658-A-C
• rs1031919395
• NM_000143.4:c.65T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-241519658-A-C
• chr1-241519658-A-G
• chr1-241519658-A-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000143.4(FH):​c.65T>G​(p.Leu22*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 33)
• Consequence: FH NM_000143.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 0.320
• Publications: 0 publications found

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]

FH Gene-Disease associations (from GenCC):

• hereditary leiomyomatosis and renal cell cancer

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• fumaric aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• pheochromocytoma-paraganglioma

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• leiomyosarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 479 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-241519658-A-C is Pathogenic according to our data. Variant chr1-241519658-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 826506.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4	c.65T>G	p.Leu22*	stop_gained	Exon 1 of 10	ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.65T>G	p.Leu22*	stop_gained	Exon 1 of 10	1	NM_000143.4	ENSP00000355518.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000724 AC: 3 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.023284), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Dec 27, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant in a gene for which loss-of-function is a known mechanism of disease; however, a downstream in-frame ATG could serve as an alternate initiator codon (Dik et al., 2016); This variant is associated with the following publications: (PMID: 27037871) -

Jul 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FH has two initiator codons, p.Met1 and p.Met44, which result in two different functional isoforms that localize to the mitochondria and cytosol, respectively (PMID: 21929734, 27037871). Loss-of-function variants in FH are known to be pathogenic (PMID: 11865300, 21398687). Variants affecting the mitochondrial isoform confer risk for fumarate hydratase deficiency, while variants that affect the cytosolic isoform confer risk for FH tumor predisposition syndrome. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FH are known to be pathogenic (PMID: 11865300, 21398687). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FH-related conditions. ClinVar contains an entry for this variant (Variation ID: 826506). This variant disrupts the mitochondria-targeting sequence (MTS) of the FH protein, which is important for protein import into the mitochondria (PMID: 27037871). This suggests that disruption of this region is causative of fumarate hydratase deficiency. For these reasons, this variant has been classified as Pathogenic for autosomal recessive fumarate hydratase deficiency. However, this variant is not likely to confer risk for autosomal dominant FH tumor predisposition syndrome. -

Fumarase deficiency Uncertain:1

Aug 30, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1

May 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L22* variant (also known as c.65T>G), located in coding exon 1 of the FH gene, results from a T to G substitution at nucleotide position 65. This changes the amino acid from a leucine to a stop codon within coding exon 1. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, there is a second in-frame methionine at p.M44. Proteins initiated from the first methionine are targeted to the mitochondrion while proteins initiated from the second methionine are targeted to the cytoplasm due to the lack of the mitochondrial targeting sequence encoded between them (Dik E et al. Traffic, 2016 Jul;17:720-32; Magrane M et al., Database (Oxford) 2011). Data suggest that it is the cytoplasmic protein that conveys the tumor suppressor function of FH (Yogev O et al. PLoS Biol., 2010 Mar;8:e1000328). This alteration and others that are expected to adversely affect the protein before the second methionine, have been observed in numerous individuals who do not have a personal or family history that is consistent with or suggestive of HLRCC (Ambry internal data). The clinical impact of this variant in terms of autosomal recessive Fumarase Deficiency is also unclear due to the lack of this variant being associated with this autosomal recessive disease in the literature and internally. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	33
DANN	Benign	0.94
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.12	N
PhyloP100		0.32
Vest4		0.62
GERP RS		0.023
PromoterAI		-0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=11/189	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1031919395; hg19: chr1-241682958;