ClinVar Miner

Submissions for variant NM_000143.4(FH):c.644A>T (p.His215Leu)

dbSNP: rs770141324
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002553885 SCV001225263 uncertain significance not provided 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 215 of the FH protein (p.His215Leu). This variant is not present in population databases (gnomAD no frequency). 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: 855318). 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.
Sema4, Sema4 RCV002255615 SCV002535567 uncertain significance Hereditary cancer-predisposing syndrome 2021-07-22 criteria provided, single submitter curation
Ambry Genetics RCV002255615 SCV002656799 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-13 criteria provided, single submitter clinical testing The p.H215L variant (also known as c.644A>T), located in coding exon 5 of the FH gene, results from an A to T substitution at nucleotide position 644. The histidine at codon 215 is replaced by leucine, 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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