rs1553341364

Positions:

• chr1-241508758-T-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000143.4(FH):​c.583A>G​(p.Met195Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,210 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M195T) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: FH NM_000143.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.67

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000143.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-241508757-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 214373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819
• PP5: Variant 1-241508758-T-C is Pathogenic according to our data. Variant chr1-241508758-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 460368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FH	NM_000143.4	c.583A>G	p.Met195Val	missense_variant	5/10	ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.583A>G	p.Met195Val	missense_variant	5/10	1	NM_000143.4	ENSP00000355518.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 18, 2022	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in affected individuals with uterine leiomyomas (PMIDs: 22473397 (2012), 25964426 (2015), and 34480341 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 13, 2022	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FH protein function. ClinVar contains an entry for this variant (Variation ID: 460368). This missense change has been observed in individual(s) with clinical features of hereditary leiomyomatosis and renal cell cancer (PMID: 22473397; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 195 of the FH protein (p.Met195Val). This variant disrupts the p.Met195 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12772087, 22764886; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Fumarase deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 23, 2024

Variant summary: FH c.583A>G (p.Met195Val) results in a conservative amino acid change located in the Fumarate lyase, N-terminal domain (IPR022761) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251098 control chromosomes. c.583A>G has been reported in the literature in five heterozygous individuals in a single family affected with Leiomyomatosis (Tolvanen_2012). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.584T>C, p.Met195Thr), supporting the critical relevance of codon 195 to FH protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 22473397). ClinVar contains an entry for this variant (Variation ID: 460368). Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2022

The p.M195V variant (also known as c.583A>G), located in coding exon 5 of the FH gene, results from an A to G substitution at nucleotide position 583. The methionine at codon 195 is replaced by valine, an amino acid with highly similar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with FH-related disease (Ambry internal data; Tolvanen J et al. Hum Reprod, 2012 Jun;27:1865-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	M
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.019	D
Polyphen		0.038	B
Vest4		0.86
MutPred		0.57		Loss of disorder (P = 0.1477);
MVP		0.95
MPC		0.43
ClinPred		0.93	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.45		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553341364; hg19: chr1-241672058;