Submissions for variant NM_001278716.2(FBXL4):c.1303C>T (p.Arg435Ter)

gnomAD frequency: 0.00004  dbSNP: rs201889294

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000056328	SCV000598187	pathogenic	Mitochondrial DNA depletion syndrome 13	2017-08-10	criteria provided, single submitter	clinical testing	The NM_012160.4:c.1303C>T (NP_036292.2:p.Arg435Ter) [GRCH38: NC_000006.12:g.98899282G>A] variant in FBXL4 gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:23993193 ; 27099744 . This variant meets one or more of the following evidence codes reported in the ACMG-guideline. PVS1:This variant is a predcted null variant in FBXL4 where loss of function is a known mechanism of disease. 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. 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 Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000604628	SCV000731341	pathogenic	Mitochondrial DNA depletion syndrome	2016-12-23	criteria provided, single submitter	clinical testing	The p.Arg435X (NM_012160.4 c.1303C>T) variant in FBXL4 has been reported in 1 ho mozygous and 2 compound heterozygous individuals with clinical features of mitoc hondrial DNA depletion syndrome 13 (Bonnen 2013, Van Rij 2016, and Prionska 2016 ). This variant has been identified in 0.012% (1/8652) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs201889294). This nonsense variant leads to a premature termination codon at position 435, which is predicted to lead to a truncated or absent protein. In su mmary, the p.Arg435X variant meets criteria to be classified as pathogenic for m itochondrial DNA depletion syndrome in an autosomal recessive manner, based upon occurrence in patients and predicted functional impact.
Ambry Genetics	RCV000622490	SCV000740716	pathogenic	Inborn genetic diseases	2014-09-03	criteria provided, single submitter	clinical testing	The c.1303C>T (p.R435*) alteration, located in exon 6 (coding exon 4) of the FBXL4 gene, consists of a C to T substitution at nucleotide position 1303. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 435. Premature stop codons are typically deleterious in nature (Richards, 2015). The heterozygous missense change is ultra rare in healthy individuals:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the FBXL4 c.1303C>T alteration was observed in 1 among 13006 total alleles studied (0.01%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. This variant is reported in the SNPDatabase as rs201889294. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV001837446	SCV002098174	pathogenic	not provided	2023-07-22	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23993193, 27290639, 30804983, 30609409, 30771478, 30369941, 27099744)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000056328	SCV002557110	pathogenic	Mitochondrial DNA depletion syndrome 13	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 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) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple individuals (ClinVar, PMID: 30771478). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
3billion, Medical Genetics	RCV000056328	SCV002573213	pathogenic	Mitochondrial DNA depletion syndrome 13	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000066091/ PMID: 23993193). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV000056328	SCV003821981	pathogenic	Mitochondrial DNA depletion syndrome 13	2022-08-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000056328	SCV005674078	pathogenic	Mitochondrial DNA depletion syndrome 13	2024-03-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001837446	SCV005834516	pathogenic	not provided	2024-09-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg435*) in the FBXL4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBXL4 are known to be pathogenic (PMID: 23993193, 23993194, 25868664). This variant is present in population databases (rs201889294, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 23993193, 27099744, 27290639, 30369941, 30771478, 30804983). ClinVar contains an entry for this variant (Variation ID: 66091). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237491	SCV005883151	pathogenic	Leigh syndrome	2024-12-06	criteria provided, single submitter	clinical testing	Variant summary: FBXL4 c.1303C>T (p.Arg435X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-05 in 250950 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FBXL4 causing Leigh Syndrome (4e-05 vs 0.00056), allowing no conclusion about variant significance. c.1303C>T has been reported in the literature in individuals affected with Mitochondrial encephalopathy (example : Bonnen_2013). These data indicate that the variant may be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 23993193). ClinVar contains an entry for this variant (Variation ID: 66091). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000056328	SCV000087497	pathogenic	Mitochondrial DNA depletion syndrome 13	2013-09-05	no assertion criteria provided	literature only