ClinVar Miner

Submissions for variant NM_001278716.2(FBXL4):c.988G>A (p.Ala330Thr)

gnomAD frequency: 0.00002  dbSNP: rs759851318
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000503443 SCV000598373 uncertain significance Mitochondrial DNA depletion syndrome 13 2017-08-10 criteria provided, single submitter reference population The NM_012160.4:c.988G>A (NP_036292.2:p.Ala330Thr) [GRCH38: NC_000006.12:g.98905541C>T] variant in FBXL4 gene is interpretated to be a Uncertain Significance - Conflicting Evidence based on ACMG guidelines (PMID: 25741868). This variant meets one or more of the following evidence codes reported in the ACMG-guideline. PM2:This variant is absent in key population databases. BP4:Computational evidence/predictors indicate no impact on the FBXL4 structure, function, or protein-protein interaction. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Uncertain Significance - Conflicting Evidence.
Labcorp Genetics (formerly Invitae), Labcorp RCV001857192 SCV002221721 uncertain significance not provided 2021-12-02 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 330 of the FBXL4 protein (p.Ala330Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with FBXL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 437670). 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 expected to disrupt FBXL4 protein function. 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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