ClinVar Miner

Submissions for variant NM_017547.4(FOXRED1):c.1261G>A (p.Val421Met)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV001090002 SCV001245045 pathogenic Mitochondrial complex 1 deficiency, nuclear type 19 2019-01-14 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_017547.3(FOXRED1):c.1261G>A, has been identified in exon 11 of 11 within the FOXRED1 gene. The variant is predicted to result in a minor amino acid change from valine to methionine at position 421 of the protein (NP_060017.1(FOXRED1):p.(Val421Met)). The valine residue at this position has moderate conservation (100 vertebrates, UCSC), and is located within the DOA (FAD dependent oxidoreductase) functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.001% (4 heterozygotes, 0 homozygotes). The variant has been previously described as pathogenic in two individuals with mitochondrial complex I deficiency (Zurita Rendom et al., (2016), Ahmed et al., (2017)). in addition, functional analysis showed the variant is the cause of an assembly deficiency in complex I, and that FOXRED1 is required for complex II assembly in myoblasts (Zurita Rendon et al., 2016). Analysis of parental samples indicated this variant was maternally inherited. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.

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