Submissions for variant NM_017547.4(FOXRED1):c.86-1G>A

gnomAD frequency: 0.00001  dbSNP: rs768720209

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196380	SCV000251515	pathogenic	not provided	2014-04-14	criteria provided, single submitter	clinical testing	c.86-1 G>A: IVS1-1 G>A in intron 1 of the FOXRED1 gene (NM_017547.3). The c.86-1 G>A splice site mutation in the FOXRED1 gene destroys the canonical splice acceptor site in intron 1. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Although this mutation has not been previously reported to our knowledge, it is expected to be a pathogenic mutation. The variant is found in MITONUC-MITOP panel(s).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001090003	SCV001245046	likely pathogenic	Mitochondrial complex 1 deficiency, nuclear type 19	2019-01-14	criteria provided, single submitter	clinical testing	A heterozygous canonical splice site variant, NM_017547.3(FOXRED1):c.86-1G>A, has been identified in intron 1 of 10 within the FOXRED1 gene. The nucleotide at this position has high conservation (Phylop UCSC). This nucleotide substitution is predicted to cause aberrant splicing of the FOXRED1 gene and may result in loss of protein function; further testing via RNA studies are required to confirm if splicing is altered. The variant is present in the gnomAD database at a frequency of 0.002% (5 heterozygotes, 0 homozygotes) and has been previously described as pathogenic (ClinVar). Analysis of parental samples indicated this variant was paternally inherited. Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC.
Invitae	RCV000196380	SCV004291347	likely pathogenic	not provided	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 1 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). This variant is present in population databases (rs768720209, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with FOXRED1-related conditions (PMID: 32573669). ClinVar contains an entry for this variant (Variation ID: 214454). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.