Submissions for variant NM_144997.7(FLCN):c.249+5G>A (rs1064793127)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485638	SCV000565005	likely pathogenic	not provided	2015-06-01	criteria provided, single submitter	clinical testing	The c.249+5 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. This 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. One in-silico splice prediction model predicted that c.249+5 G>A destroys the natural splicing donor site of intron 4. Additionally, this substitution occurs at a position that is well conserved in vertebrates. Therefore, this variant is a strong candidate for a pathogenic variant; however, the possibility that it is a benign variant cannot be excluded
Invitae	RCV000635570	SCV000756989	uncertain significance	Multiple fibrofolliculomas	2017-12-14	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the FLCN gene. It does not directly change the encoded amino acid sequence of the FLCN protein, but it affects a nucleotide within the consensus splice site of the intron. 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: 418211). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, 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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