ClinVar Miner

Submissions for variant NM_017547.4(FOXRED1):c.694C>T (p.Gln232Ter) (rs267606829)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000578659 SCV000680696 pathogenic not provided 2017-12-07 criteria provided, single submitter clinical testing The Q232X variant in the FOXRED1 gene has been reported previously in Leigh syndrome, in an affected individual who was compound heterozygous for the Q232X variant and another FOXRED1 variant (Calvo et al., 2010). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q232X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret Q232X as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV001194045 SCV001363290 pathogenic Leigh syndrome 2019-12-30 criteria provided, single submitter clinical testing Variant summary: FOXRED1 c.694C>T (p.Gln232X) 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. At least one publication reports experimental evidence that this variant affects mRNA splicing as evidenced by analysis of patient cDNA showing occasional skipping of exon 6, resulting in a transcript predicted to lack 40 internal residues (Calvo_2010). The variant allele was found at a frequency of 1.2e-05 in 251184 control chromosomes. c.694C>T has been reported in the literature in at-least one individual affected with Leigh syndrome (example, Calvo_2010). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in defects in human mitochondrial complex I biogenesis (Formosa_2015). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000000015 SCV000020158 pathogenic Mitochondrial complex 1 deficiency, nuclear type 19 2010-10-01 no assertion criteria provided literature only

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