Submissions for variant NM_001278716.2(FBXL4):c.1304G>A (p.Arg435Gln)

gnomAD frequency: 0.00002  dbSNP: rs754142863

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493951	SCV000583275	likely pathogenic	not provided	2021-04-01	criteria provided, single submitter	clinical testing	Identified in two patients who were also heterozygous for a second missense variant in FBXL4 and had features consistent with encephalomyopathic mitochondrial DNA depletion syndrome in published literature (Huemer et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32154989, 10531035, 25868664, 28940506, 23993194, 23993193, 27743463)
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000501572	SCV000598163	likely pathogenic	Mitochondrial DNA depletion syndrome 13	2017-08-10	criteria provided, single submitter	clinical testing	The NM_012160.4:c.1304G>A (NP_036292.2:p.Arg435Gln) [GRCH38: NC_000006.12:g.98899281C>T] variant in FBXL4 gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:25868664 . 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. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 13 which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 13 in multiple affected family members. PP2:This is a missense variant in FBXL4 with a low rate of benign and high rate of pathogenic missense variations. PP4:Patient’s phenotype or family history is highly specific for FBXL4. PP5:Reputable source(s) suggest that the variant is pathogenic. Based on this evidence code ClinGen Pathogenicity Calculator (PMID:28081714) suggested that the variant is Likely Pathogenic.
Ambry Genetics	RCV000623300	SCV000741866	pathogenic	Inborn genetic diseases	2016-10-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000493951	SCV003439478	uncertain significance	not provided	2022-05-17	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. This variant disrupts the p.Arg435 amino acid residue in FBXL4. Other variant(s) that disrupt this residue have been observed in individuals with FBXL4-related conditions (PMID: 25868664, 28940506), which suggests that this may be a clinically significant amino acid residue. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 435 of the FBXL4 protein (p.Arg435Gln). This variant is present in population databases (rs754142863, gnomAD 0.006%). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 25868664). ClinVar contains an entry for this variant (Variation ID: 430470). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782406	SCV005395139	likely pathogenic	Leigh syndrome	2024-09-09	criteria provided, single submitter	clinical testing	Variant summary: FBXL4 c.1304G>A (p.Arg435Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250918 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1304G>A has been reported in the literature in at least two compound heterozygotes and one homozygote affected with complex multisystem mitochondrial disorders (e.g., Huemer_2015, Forny_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34056100, 25868664). ClinVar contains an entry for this variant (Variation ID: 430470). Based on the evidence outlined above, the variant was classified as likely pathogenic.