1-241519722-T-G

Variant names:

• chr1-241519722-T-G
• rs776806414
• NM_000143.4:c.1A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 11P and 4B. PVS1 PS1_Moderate PP5 BS2

The NM_000143.4(FH):​c.1A>C​(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.0000158 in 1,391,288 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: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: FH NM_000143.4 initiator_codon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:4
• Conservation: PhyloP100: 4.13

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 21 pathogenic variants. Next in-frame start position is after 129 CDS bases. Genomic position: 241519594. Lost 0.084 part of the original CDS.
• PS1: Another start lost variant in NM_000143.4 (FH) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 1502868
• PP5: Variant 1-241519722-T-G is Pathogenic according to our data. Variant chr1-241519722-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 296878.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=3}.
• BS2: High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4	c.1A>C	p.Met1?	initiator_codon_variant	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.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 10	1	NM_000143.4	ENSP00000355518.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000136 AC: 2 AN: 146594 Hom.: 0 AF XY: 0.0000128 AC XY: 1 AN XY: 78404

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000451

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 22 AN: 1391288 Hom.: 0 Cov.: 31 AF XY: 0.0000204 AC XY: 14 AN XY: 685372

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: 0.0000205

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fumarase deficiency Pathogenic:2 Uncertain:1

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with fumarase deficiency (MIM#606812) and leiomyomatosis and renal cell cancer (MIM#150800). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). Autosomal dominant hereditary leiomyomatosis and renal cell cancer (MIM#150800) has been associated with the cytosolic isoform (PMIDs: 20231875, 21398687, 28300276). (I) 0206 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG). The first 43 amino acid residues encode the mitochondrial targeting sequence, followed by an alternative initiation codon p.Met44 (PMID: 27037871). This variant is expected to affect the mitochondrial isoform, but not the cytosolic isoform. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 2 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position has been observed in gnomAD (v2) (highest allele count: 3 heterozygotes, 0 homozygotes). (I) 0708 - Other start-loss variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. p.(Met1Val), p.(Met1Leu), p.(Met1Arg), p.(Met1Thr) and p.(Met1Lys) have been classified as both likely pathogenic and variants of uncertain significance, and p.(Met1Ile) has been classified as likely pathogenic by clinical laboratories (ClinVar). In addition, p.(Met1Val) has been reported once in a heterozygous individual with urothelial carcinoma without renal cell carcinoma (PMID: 31844177). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported twice as likely pathogenic and twice as a variant of uncertain significance by clinical laboratories (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Sep 01, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary leiomyomatosis and renal cell cancer Uncertain:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Oct 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the FH mRNA. The next in-frame methionine is located at codon 44. 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. This variant is present in population databases (no rsID available, gnomAD 0.004%). 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: 296878). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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;C1708350:Hereditary leiomyomatosis and renal cell cancer Pathogenic:1

Apr 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? variant (also known as c.1A>C), located in coding exon 1 of the FH gene, results from a A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an alternate in-frame methionine 44 amino acids from the initiation site. 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; bar009). 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 nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	24
DANN	Benign	0.90
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.0	D
PROVEAN	Benign	-0.20	N
REVEL	Pathogenic	0.68
Sift	Benign	0.20	T
Sift4G	Benign	0.21	T
Polyphen		0.17	B
Vest4		0.90
MutPred		0.64		Loss of methylation at R3 (P = 0.0929);
MVP		0.94
ClinPred		0.93	D
GERP RS		5.3
Varity_R		0.24
gMVP		0.58

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: rs776806414; hg19: chr1-241683022;