ClinVar Miner

Submissions for variant NM_000143.4(FH):c.1259C>T (p.Ala420Val)

gnomAD frequency: 0.00001  dbSNP: rs766377516
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002543121 SCV001494437 uncertain significance not provided 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 420 of the FH protein (p.Ala420Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 1007873). 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 95%. 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 RCV002486186 SCV002793780 uncertain significance Fumarase deficiency; Hereditary leiomyomatosis and renal cell cancer 2021-08-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV003166728 SCV003908044 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-10 criteria provided, single submitter clinical testing The p.A420V variant (also known as c.1259C>T), located in coding exon 9 of the FH gene, results from a C to T substitution at nucleotide position 1259. The alanine at codon 420 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Natera, Inc. RCV001305118 SCV002085299 uncertain significance Fumarase deficiency 2020-02-21 no assertion criteria provided clinical testing

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