Submissions for variant NM_001278716.2(FBXL4):c.1444C>T (p.Arg482Trp)

gnomAD frequency: 0.00003  dbSNP: rs398123061

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224233	SCV000280648	likely pathogenic	not provided	2014-07-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000224233	SCV000583379	pathogenic	not provided	2023-11-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27182039, 23993194, 27743463, 34052969)
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000056330	SCV000598168	likely pathogenic	Mitochondrial DNA depletion syndrome 13	2017-08-10	criteria provided, single submitter	clinical testing	The NM_012160.4:c.1444C>T (NP_036292.2:p.Arg482Trp) [GRCH38: NC_000006.12:g.98875673G>A] variant in FBXL4 gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:23993194 ; 25868664 ; 27743463 . 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. PP3:Computational evidence/predictors indicate the variant has deleterious effect on FBXL4 structure, function, or protein-protein interaction. 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.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000056330	SCV001430104	pathogenic	Mitochondrial DNA depletion syndrome 13	2019-10-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224233	SCV002062692	likely pathogenic	not provided	2023-02-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000224233	SCV002242773	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 482 of the FBXL4 protein (p.Arg482Trp). This variant is present in population databases (rs398123061, gnomAD 0.005%). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 23993194, 25868664, 27743463). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66093). 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 FBXL4 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000056330	SCV002768918	likely pathogenic	Mitochondrial DNA depletion syndrome 13	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) (MIM#615471). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Affected individuals carrying the same variant have been reported to display clinical variability (PMID: 30804983). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 8 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.R482Q: 111 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated leucine-rich repeat region 5 (PMID: 28940506; Uniprot). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.R482Q variant has been classified as variant of uncertain significance (LOVD; PMID: 28940506). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in two individuals with early-onset mitochondrial encephalomyopathy and mitochondrial maintenance defect, respectively, and has been reported as either likely pathogenic or pathogenic by clinical diagnostic laboratories (ClinVar; PMIDs: 23993194, 25868664). (SP) 0906 - Segregation evidence for this variant is inconclusive. There is insufficient information to determine segregation of this variant (PMID: 23993194). (I) 1010 - Functional evidence for this variant is inconclusive. Fibroblasts from a homozygous carrier of this variant demonstrated reduced mitochondrial DNA amount compared to the mean value of controls; however, the standard deviation was within with the control range (PMID: 23993194). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV000056330	SCV003836023	pathogenic	Mitochondrial DNA depletion syndrome 13	2022-12-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155062	SCV003844383	pathogenic	Leigh syndrome	2024-07-15	criteria provided, single submitter	clinical testing	Variant summary: FBXL4 c.1444C>T (p.Arg482Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249996 control chromosomes (gnomAD and publication data). c.1444C>T has been reported in the literature in multiple individuals affected with Early-Onset Mitochondrial Encephalomyopathy, including homozygotes (Gai_2013, Alazami_2014, Huemer_2015). These data indicate that the variant is very 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: 25558065, 23993194, 25868664). ClinVar contains an entry for this variant (Variation ID: 66093). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV003242974	SCV003951283	pathogenic	Inborn genetic diseases	2023-03-15	criteria provided, single submitter	clinical testing	The c.1444C>T (p.R482W) alteration is located in exon 8 (coding exon 6) of the FBXL4 gene. This alteration results from a C to T substitution at nucleotide position 1444, causing the arginine (R) at amino acid position 482 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.003% (8/281146) total alleles studied. The highest observed frequency was 0.01% (2/19936) of East Asian alleles. This variant has been reported as homozygous in three siblings and one unrelated individual with features consistent with FBXL4-related mitochondrial DNA depletion syndrome (Gai, 2013; Forny, 2021). In addition, this variant has been reported compound heterozygous with other FBXL4 variants in multiple affected individuals (Dai, 2016; Martin-Saavedra, 2022). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
OMIM	RCV000056330	SCV000087499	pathogenic	Mitochondrial DNA depletion syndrome 13	2013-09-05	no assertion criteria provided	literature only
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000162170	SCV000196456	likely pathogenic	Mitochondrial encephalomyopathy; Global developmental delay	2014-12-01	no assertion criteria provided	research