ClinVar Miner

Submissions for variant NM_000143.4(FH):c.1405G>A (p.Ala469Thr)

gnomAD frequency: 0.00001  dbSNP: rs1060500906
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002525543 SCV000544283 uncertain significance not provided 2021-08-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 469 of the FH protein (p.Ala469Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with FH-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Baylor Genetics RCV000457993 SCV005057754 uncertain significance Fumarase deficiency 2024-03-05 criteria provided, single submitter clinical testing
GeneDx RCV002525543 SCV005385210 uncertain significance not provided 2024-01-04 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV004948311 SCV005585584 uncertain significance Hereditary cancer-predisposing syndrome 2024-11-05 criteria provided, single submitter clinical testing The p.A469T variant (also known as c.1405G>A), located in coding exon 10 of the FH gene, results from a G to A substitution at nucleotide position 1405. The alanine at codon 469 is replaced by threonine, an amino acid with similar properties. 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 available evidence, the clinical significance of this variant remains unclear.
Natera, Inc. RCV000457993 SCV002085285 uncertain significance Fumarase deficiency 2021-03-10 no assertion criteria provided clinical testing

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