Submissions for variant NM_001278716.2(FBXL4):c.1025C>G (p.Ser342Cys)

gnomAD frequency: 0.00001  dbSNP: rs780707718

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000500631	SCV000598380	uncertain significance	Mitochondrial DNA depletion syndrome 13	2017-08-10	criteria provided, single submitter	reference population	The NM_012160.4:c.1025C>G (NP_036292.2:p.Ser342Cys) [GRCH38: NC_000006.12:g.98905504G>C] 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.
GeneDx	RCV001753846	SCV001987957	uncertain significance	not provided	2019-09-10	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV001753846	SCV003494200	uncertain significance	not provided	2022-06-22	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 373158). This variant has not been reported in the literature in individuals affected with FBXL4-related conditions. This variant is present in population databases (rs780707718, gnomAD 0.07%). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 342 of the FBXL4 protein (p.Ser342Cys).
GeneDx	RCV000413651	SCV000491727	uncertain significance	not specified	2016-11-28	flagged submission	clinical testing	The S342C variant in the FBXL4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S342C 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. The S342C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret S342C as a variant of uncertain significance.