rs786202907

Positions:

• chr1-241508741-TGCA-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_000143.4(FH):​c.597_599delTGC​(p.Ala200del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A199A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FH NM_000143.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.81

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000143.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000143.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-241508741-TGCA-T is Pathogenic according to our data. Variant chr1-241508741-TGCA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 186384.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FH	NM_000143.4	c.597_599delTGC	p.Ala200del	disruptive_inframe_deletion	5/10	ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.597_599delTGC	p.Ala200del	disruptive_inframe_deletion	5/10	1	NM_000143.4	ENSP00000355518.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2024

The c.597_599delTGC variant (also known as p.A199del) is located in coding exon 5 of the FH gene. This variant results from an in-frame deletion of 3 nucleotides (TGC) at positions 597 to 599, causing the removal of a highly-conserved alanine residue at codon 199. This variant has been detected in multiple individuals who meet clinical diagnostic criteria for HLRCC (Ambry internal data). Based on internal structural analysis, this variant is anticipated to disrupt a region of known function (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al., PLoS ONE 2012; 7(10):e46688). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 186384). This variant has been observed in individual(s) with clinical features of FH-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This variant, c.597_599del, results in the deletion of 1 amino acid(s) of the FH protein (p.Ala200del), but otherwise preserves the integrity of the reading frame. -

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: rs786202907; hg19: chr1-241672041;