ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.991T>C (p.Ser331Pro)

dbSNP: rs2144895251
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001364331 SCV001560473 uncertain significance Birt-Hogg-Dube syndrome 2023-12-29 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 331 of the FLCN protein (p.Ser331Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FLCN-related conditions. ClinVar contains an entry for this variant (Variation ID: 1055627). 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 FLCN protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV002384521 SCV002695867 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-08 criteria provided, single submitter clinical testing The p.S331P variant (also known as c.991T>C), located in coding exon 6 of the FLCN gene, results from a T to C substitution at nucleotide position 991. The serine at codon 331 is replaced by proline, an amino acid with similar properties. This amino acid position is poorly 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.
Johns Hopkins Genomics, Johns Hopkins University RCV003320376 SCV004024523 uncertain significance Familial spontaneous pneumothorax 2023-06-06 criteria provided, single submitter clinical testing This FLCN missense variant is absent from a large population dataset. It has been reported in ClinVar (Variation ID 1055627), but has not been reported in the literature, to our knowledge. Two bioinformatic tools queried predict that this substitution would be tolerated, and the serine residue at this position is evolutionarily conserved across only a few of the species assessed. We consider the clinical significance of c.991T>C in FLCN to be uncertain at this time.
GeneDx RCV003442872 SCV004170660 uncertain significance not provided 2023-10-05 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function
Baylor Genetics RCV001364331 SCV004195357 uncertain significance Birt-Hogg-Dube syndrome 2023-06-09 criteria provided, single submitter clinical testing

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