ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1271T>C (p.Val424Ala)

gnomAD frequency: 0.00004  dbSNP: rs752170592
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001214989 SCV001386705 uncertain significance Birt-Hogg-Dube syndrome 2024-01-13 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 424 of the FLCN protein (p.Val424Ala). This variant is present in population databases (rs752170592, gnomAD 0.003%). 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: 944564). 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 RCV002375180 SCV002688507 likely benign Hereditary cancer-predisposing syndrome 2022-04-26 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx RCV002462832 SCV002757721 uncertain significance not provided 2022-11-15 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17028174)
PreventionGenetics, part of Exact Sciences RCV003393892 SCV004119581 uncertain significance FLCN-related condition 2023-03-03 criteria provided, single submitter clinical testing The FLCN c.1271T>C variant is predicted to result in the amino acid substitution p.Val424Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-17119723-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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