Submissions for variant NM_001278716.2(FBXL4):c.1622C>T (p.Thr541Ile)

gnomAD frequency: 0.00006  dbSNP: rs1391578014

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000500362	SCV000598171	likely pathogenic	Mitochondrial DNA depletion syndrome 13	2017-08-10	criteria provided, single submitter	clinical testing	The NM_012160.4:c.1622C>T (NP_036292.2:p.Thr541Ile) [GRCH38: NC_000006.12:g.98875495G>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: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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155218	SCV003844281	uncertain significance	not specified	2023-02-27	criteria provided, single submitter	clinical testing	Variant summary: FBXL4 c.1622C>T (p.Thr541Ile) results in a non-conservative amino acid change located in the Leucine-Rich Repeats (El-Hattab_2017) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251002 control chromosomes (gnomAD). c.1622C>T has been reported in the literature in individuals affected with lactic acidemia and mitochondrial disorder (Dai_2017, El-Hattab_2017, Ballout_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites this variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.