ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1274A>G (p.Gln425Arg) (rs786203348)

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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 RCV000166621 SCV000217425 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-28 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient or conflicting evidence
Invitae RCV000635548 SCV000756964 uncertain significance Multiple fibrofolliculomas 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 425 of the FLCN protein (p.Gln425Arg). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FLCN-related disease. ClinVar contains an entry for this variant (Variation ID: 186952). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Johns Hopkins Genomics,Johns Hopkins University RCV000635548 SCV001167206 uncertain significance Multiple fibrofolliculomas 2019-10-07 criteria provided, single submitter clinical testing This FLCN variant (rs786203348) is rare (<0.1%) in a large population dataset (gnomAD: 9/280056 total alleles; 0.0032%; no homozygotes). This variant has not been reported in the literature, to our knowledge. Two submitters in ClinVar classify c.1274A>G as a variant of uncertain clinical significance. Three bioinformatic tools queried predict that this substitution would be tolerated, and the glutamine residue at this position is poorly evolutionarily conserved across species assessed. Due to lack of funtional and segregation studies, we consider the clinical significance of c.1274A>G to be uncertain at this time.

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