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

gnomAD frequency: 0.00004  dbSNP: rs267606829

Total submissions: 6

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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Fulgent Genetics, Fulgent Genetics	RCV000000015	SCV002793147	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 19	2022-03-29	criteria provided, single submitter	clinical testing
Invitae	RCV000578659	SCV002982300	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln232*) in the FOXRED1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FOXRED1 are known to be pathogenic (PMID: 20818383, 20858599). This variant is present in population databases (rs267606829, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Leigh syndrome (PMID: 20818383). ClinVar contains an entry for this variant (Variation ID: 5). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003390625	SCV004119439	pathogenic	FOXRED1-related condition	2022-10-31	criteria provided, single submitter	clinical testing	The FOXRED1 c.694C>T variant is predicted to result in premature protein termination (p.Gln232*). This variant was reported in individuals with mitochondrial complex I deficiency (Calvo et al. 2010. PubMed ID: 20818383, supplementary data; Formosa et al. 2015. PubMed ID: 25678554; Apatean et al. 2019. PubMed ID: 30723688). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-126145284-C-T). Nonsense variants in FOXRED1 are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000000015	SCV000020158	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 19	2010-10-01	no assertion criteria provided	literature only