Submissions for variant NM_017547.4(FOXRED1):c.733+1G>A

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Diagnostic and Treatment Unit for Congenital Metabolic Diseases, Hopital Clínico Universitario de Santiago de Compostela (CHUS)	RCV002283347	SCV002571712	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 19	2019-08-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002283347	SCV002766399	likely pathogenic	Mitochondrial complex 1 deficiency, nuclear type 19	2022-11-10	criteria provided, single submitter	clinical testing	Variant summary: FOXRED1 c.733+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 250948 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in FOXRED1 causing Mitochondrial Complex 1 Deficiency, Nuclear Type 19, allowing no conclusion about variant significance. c.733+1G>A has been reported in the literature in a family affected with Mitochondrial Complex 1 Deficiency (Barbosa-Gouveia_2019), and these affected individuals were reported as compound heterozygous with another possibly pathogenic variant. 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 clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003728066	SCV004535561	pathogenic	not provided	2023-05-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1705022). Disruption of this splice site has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 31434271). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs754952690, gnomAD 0.03%). This sequence change affects a donor splice site in intron 6 of the FOXRED1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FOXRED1 are known to be pathogenic (PMID: 20818383, 20858599).
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV002283347	SCV004809566	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 19	2024-04-04	criteria provided, single submitter	clinical testing