rs1060499635

Variant names:

• chr1-241508757-ATTGCTG-A
• rs1060499635
• NM_000143.4:c.578_583delCAGCAA

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM4 PP3 PP5_Very_Strong

The NM_000143.4(FH):​c.578_583delCAGCAA​(p.Thr193_Ala194del) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FH NM_000143.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.60

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 15 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 1-241508757-ATTGCTG-A is Pathogenic according to our data. Variant chr1-241508757-ATTGCTG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 393568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FH	NM_000143.4	c.578_583delCAGCAA	p.Thr193_Ala194del	disruptive_inframe_deletion	Exon 5 of 10	ENST00000366560.4	NP_000134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FH	ENST00000366560.4	c.578_583delCAGCAA	p.Thr193_Ala194del	disruptive_inframe_deletion	Exon 5 of 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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary leiomyomatosis and renal cell cancer Pathogenic:1

Jan 17, 2017

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jun 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.578_583del, results in the deletion of 2 amino acid(s) of the FH protein (p.Thr193_Ala194del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with FH-related conditions (PMID: 22982371). This variant is also known as c.449_454del6 (p.Thr150_Ala151del). ClinVar contains an entry for this variant (Variation ID: 393568). This variant disrupts a region of the FH protein in which other variant(s) (Thr193Ile) have been determined to be pathogenic (PMID: 24346898; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 08, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.578_583delCAGCAA variant (also known as p.T193_A194del) is located in coding exon 5 of the FH gene. This variant results from an in-frame CAGCAA deletion at nucleotide positions 578 to 583. This results in the in-frame deletion of threonine and alanine at codons 193 and 194, respectively. This variant has been observed in multiple individuals who have a personal or family history that is consistent with FH-associated disease and it segregates with those diseases in multiple families (Shuch B et al. J. Urol. 2013 Feb;189:430-5; Ambry internal data). This variant has also been referred to as FH c.449_454del6 in the literature. This variant is structurally destabilizing and the deletion is likely to be as disruptive or more disruptive as some nearby, known pathogenic alterations in FH (Pereira de Pádua RA et al. Acta Crystallogr F Struct Biol Commun. 2014 Jan;70:120-2; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). These amino acid positions are highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060499635; hg19: chr1-241672057;