ClinVar Miner

Submissions for variant NM_000371.4(TTR):c.25C>T (p.Leu9Phe)

gnomAD frequency: 0.00001  dbSNP: rs762243340
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236970 SCV000292797 uncertain significance not provided 2015-04-21 criteria provided, single submitter clinical testing The L9F variant has not been published as a pathogenic mutation, nor has it been reported as a benign polymorphism to our knowledge. The L9F variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the L9F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, no missense mutations in nearby residues have been reported in the Human Gene Mutation Database in association with amyloidosis (Stenson et al., 2014), suggesting this region of the protein may be tolerant of change.
Labcorp Genetics (formerly Invitae), Labcorp RCV000647356 SCV000769148 uncertain significance Amyloidosis, hereditary systemic 1 2017-12-06 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TTR-related disease. ClinVar contains an entry for this variant (Variation ID: 245725). This variant is present in population databases (rs762243340, ExAC 0.001%). This sequence change replaces leucine with phenylalanine at codon 9 of the TTR protein (p.Leu9Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine.

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