ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.977C>T (p.Pro326Leu) (rs138031155)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567800 SCV000664606 likely benign Hereditary cancer-predisposing syndrome 2017-10-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
GeneDx RCV000613024 SCV000728439 likely benign not specified 2018-01-18 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina RCV000264762 SCV000401002 uncertain significance Multiple fibrofolliculomas 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000319945 SCV000401003 uncertain significance Spontaneous pneumothorax 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589923 SCV000699936 likely benign not provided 2016-08-31 criteria provided, single submitter clinical testing Variant summary: The FLCN c.977C>T (p.Pro326Leu) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 22/121304 control chromosomes at a frequency of 0.0001814, which is approximately 145 times the estimated maximal expected allele frequency of a pathogenic FLCN variant (0.0000013), suggesting this variant is likely a benign polymorphism. However, only 22 allele carriers were reported in this dataset, which is not a large enough number to definitively classify this variant as benign in the absence of other information. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign.
Invitae RCV000264762 SCV000549441 uncertain significance Multiple fibrofolliculomas 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 326 of the FLCN protein (p.Pro326Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs138031155, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with an FLCN-related disease. ClinVar contains an entry for this variant (Variation ID: 322065). 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 leucine 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. 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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