ClinVar Miner

Submissions for variant NM_017547.4(FOXRED1):c.612_615dup (p.Ala206fs) (rs398124308)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000190588 SCV000245613 likely pathogenic Mitochondrial complex I deficiency 2014-07-08 criteria provided, single submitter clinical testing The Ala206SerfsX15 variant has been identified in 0.012% (1/8254) of European American chromosomes and 0.023% (1/4264) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). The same frameshift variant (but from a different nucleotide variant) in FOXRED1 has been reported in 1 individual with mitochondrial complex I deficiency (Haack 2012). This individual was compound heterozygous. The Ala206SerfsX15 frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 206 and lead to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant is likely to be pathogenic, though additional data are required to fully establish the role of the FOXRED1 gene in disease given limited studies to date.
GeneDx RCV000081797 SCV000251514 pathogenic not provided 2018-10-22 criteria provided, single submitter clinical testing c.612_615dupAGTG: p.Ala206SerfsX15 (A206SfsX15) in exon 5 of the FOXRED1 gene (NM_017547.3). The normal sequence with the bases that are duplicated in braces is: AGGG{AGTG}GCTT. The c.612_615dupAGTG pathogenic variant in the FOXRED1 gene has been reported previously in association with mitochondrial complex I deficiency in a patient who harbored c.612_615dupAGTG and another FOXRED1 pathogenic variant (Haack et al., 2012). The duplication causes a frameshift starting with codon Alanine 206, changes this amino acid to a Serine residue and creates a premature Stop codon at position 15 of the new reading frame, denoted p.Ala206SerfsX15. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in MITONUC-MITOP panel(s).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000081797 SCV000331442 likely pathogenic not provided 2015-10-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586362 SCV000699430 pathogenic Leigh syndrome 2016-10-24 criteria provided, single submitter clinical testing Variant summary: The FOXRED1 c.612_615dupAGTG (p.Ala206Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent FOXRED1 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If NMD is escaped, this variant is predicted to truncate Glycine/D-amino acid oxidase domain. Truncation downstream of this position has also been reported (PMID: 20818383). This variant was found in 24/120958 control chromosomes at a frequency of 0.0001984, which does not exceed the estimated maximal expected allele frequency of a pathogenic FOXRED1 variant (0.00125). This variant has been reported in literature in one patient with mitochondrial complex I deficiency in compound heterozygous state with p.R136W variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000778312 SCV000914495 uncertain significance Mitochondrial complex I deficiency, nuclear type 1 2017-09-22 criteria provided, single submitter clinical testing The FOXRED1 c.612_615dupAGTG (p.Ala206SerfsTer15) variant results in a frameshift variant predicted to result in premature termination of the protein. The p.Ala206SerfsTer15 variant has been reported in one individual with mitochondrial complex I deficiency in a compound heterozygous state with a known likely pathogenic missense variant (Haack et al. 2012). The age of onset of disease in this individual was before six months of age, with the disease course described as progressive. The individual was reported to have less than 25% of complex 1 activity compared to controls. The p.Ala206SerfsTer15 variant was also identified in one healthy individual in a heterozygous state (Vassy et al. 2017). The p.Ala206SerfsTer15 variant was absent from 200 control chromosomes and is reported at a frequency of 0.00069 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence and the potential impact of frameshift variants, the p.Ala206SerfsTer15 variant is classified as a variant of unknown significance but suspicious for pathogenicity for mitochondrial complex I deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000081797 SCV001248734 pathogenic not provided 2017-02-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197098 SCV001367734 pathogenic Mitochondrial complex 1 deficiency, nuclear type 19 2019-01-16 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000081797 SCV001447939 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
New York Genome Center RCV001197098 SCV001622885 likely pathogenic Mitochondrial complex 1 deficiency, nuclear type 19 2020-05-07 criteria provided, single submitter clinical testing

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