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

dbSNP: rs398124308

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2023-05-03	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22200994, 30956948, 31589614, 33613441, 30723688, 31065540)
Eurofins Ntd Llc (ga)	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 Laboratory Services, 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 Center for Human Genetics 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	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 19	2021-05-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001197098	SCV002025164	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 19	2023-04-24	criteria provided, single submitter	clinical testing
DASA	RCV000778312	SCV002061208	pathogenic	Mitochondrial complex I deficiency, nuclear type 1	2022-01-05	criteria provided, single submitter	clinical testing	The c.612_615dup;p.(Ala206Serfs*15) is a null frameshift variant (NMD) in the FOXRED1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 95754; PMID: 33613441; 31065540; 22200994; 30723688; 30956948; 31589614) - PS4. The variant is present at low allele frequencies population databases (rs398124308– gnomAD 0.01314%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Ala206Serfs*15) was detected in trans with a pathogenic variant(PMID: 22200994, 30723688, 31065540) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.
MGZ Medical Genetics Center	RCV001197098	SCV002579136	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 19	2022-04-20	criteria provided, single submitter	clinical testing
Invitae	RCV000081797	SCV002966029	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala206Serfs*15) 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 (rs765593341, gnomAD 0.07%). This premature translational stop signal has been observed in individuals with mitochondrial complex I deficiency (PMID: 22200994, 31065540). ClinVar contains an entry for this variant (Variation ID: 95754). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002513837	SCV003677259	pathogenic	Inborn genetic diseases	2022-01-25	criteria provided, single submitter	clinical testing	The c.612_615dupAGTG (p.A206Sfs*15) alteration, located in exon 5 (coding exon 5) of the FOXRED1 gene, consists of a duplication of AGTG at position 612, causing a translational frameshift with a predicted alternate stop codon after 15 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been detected with another mutation in patients with FOXRED1-related mitochondrial complex I deficiency (Ahmed, 2017; Apatean, 2019; Haack, 2012). Based on the available evidence, this alteration is classified as pathogenic.