Submissions for variant NM_000143.4(FH):c.700A>G (p.Thr234Ala)

gnomAD frequency: 0.00001  dbSNP: rs372505976

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163828	SCV000214414	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-28	criteria provided, single submitter	clinical testing	The p.T234A variant (also known as c.700A>G), located in coding exon 5 of the FH gene, results from an A to G substitution at nucleotide position 700. The threonine at codon 234 is replaced by alanine, an amino acid with similar properties. This alteration has been identified in numerous patients with a personal and/or family history of pheochromocytomas or paragangliomas, including tumors with a loss of fumarate hydratase staining in immunohistochemistry experiments (Ambry internal data; Richter S et al. Genet. Med. 2018 Jul; Fuchs TL et al. Am J Surg Pathol 2023 Jan;47(1):25-36; Zavoshi S et al. Urology 2023 Feb.). Based on internal structural analysis, this amino acid sits at the interface of two monomer subunits and this substitution is anticipated to result in a significant decrease in structural stability (Baugh L et al. Tuberculosis (Edinb). 2015 Mar;95:142-8; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation in association with PPGL, however its association with other features of hereditary leiomyomatosis and renal cell carcinoma syndrome is unclear.
GeneDx	RCV000195694	SCV000251467	likely pathogenic	not provided	2023-06-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30050099, 36773955, 24334767, 28552549, 25004247, 34994643, 35993574, 31212687)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195694	SCV000632487	pathogenic	not provided	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 234 of the FH protein (p.Thr234Ala). This variant is present in population databases (rs372505976, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of hereditary leiomyomatosis and renal cell cancer (HLRCC) and/or pheochromocytoma (PMID: 30050099; external communication, internal data). ClinVar contains an entry for this variant (Variation ID: 184555). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FH protein function with a positive predictive value of 95%. This variant disrupts the p.Thr234 amino acid residue in FH. Other variant(s) that disrupt this residue have been observed in individuals with FH-related conditions (internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002498811	SCV002794636	likely pathogenic	Fumarase deficiency; Hereditary leiomyomatosis and renal cell cancer	2021-11-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003316008	SCV004018711	likely pathogenic	Hereditary leiomyomatosis and renal cell cancer	2023-07-10	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 34994643, 30050099, 36773955].
Baylor Genetics	RCV003467282	SCV004197341	pathogenic	Fumarase deficiency	2023-07-22	criteria provided, single submitter	clinical testing