ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.134C>T (p.Ala45Val) (rs556510460)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564102 SCV000673477 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-06 criteria provided, single submitter clinical testing The p.A45V variant (also known as c.134C>T), located in coding exon 1 of the FLCN gene, results from a C to T substitution at nucleotide position 134. The alanine at codon 45 is replaced by valine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001171925 SCV001334829 uncertain significance not provided 2020-02-01 criteria provided, single submitter clinical testing
Invitae RCV001246934 SCV001420327 uncertain significance Multiple fibrofolliculomas 2020-03-18 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 45 of the FLCN protein (p.Ala45Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs556510460, ExAC 0.03%). This variant has not been reported in the literature in individuals with FLCN-related conditions. ClinVar contains an entry for this variant (Variation ID: 485613). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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