ClinVar Miner

Submissions for variant NM_000143.4(FH):c.776T>C (p.Met259Thr)

gnomAD frequency: 0.00001  dbSNP: rs1407485828
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002608023 SCV002274439 uncertain significance not provided 2023-11-20 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 259 of the FH protein (p.Met259Thr). This variant is present in population databases (no rsID available, gnomAD 0.06%). 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: 1488936). 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 not expected to disrupt FH protein function with a negative predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics RCV002486553 SCV002783142 uncertain significance Fumarase deficiency; Hereditary leiomyomatosis and renal cell cancer 2021-12-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV004045275 SCV005032749 uncertain significance Hereditary cancer-predisposing syndrome 2024-02-01 criteria provided, single submitter clinical testing The p.M259T variant (also known as c.776T>C), located in coding exon 6 of the FH gene, results from a T to C substitution at nucleotide position 776. The methionine at codon 259 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.

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