ClinVar Miner

Submissions for variant NM_024417.5(FDXR):c.1156C>T (p.Arg386Trp)

gnomAD frequency: 0.00002  dbSNP: rs760345680
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623158 SCV000741375 pathogenic Inborn genetic diseases 2017-10-12 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002470935 SCV002767780 likely pathogenic Auditory neuropathy-optic atrophy syndrome 2020-10-19 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with auditory neuropathy and optic atrophy (MIM#617717). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (45 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (6 heterozygotes, 0 homozygotes). (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the annotated NAD(P) binding domain (PMID: 29040572). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple homozygous patients with mitochondriopathy with optic atrophy (ClinVar, PMID: 29040572). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. This variant causes reduced enzyme activity and overall mitochondrial dysfunction. Defects were rescued by overexpression of WT FDXR (PMID: 29040572). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics RCV002470935 SCV002796654 pathogenic Auditory neuropathy-optic atrophy syndrome 2021-10-05 criteria provided, single submitter clinical testing
Baylor Genetics RCV002470935 SCV003835487 pathogenic Auditory neuropathy-optic atrophy syndrome 2023-12-13 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV003411472 SCV004045999 pathogenic FDXR-related disorder criteria provided, single submitter clinical testing This variant is also known as p.Arg386Trp, p.Arg392Trp, or p.Arg378Trp in the literature. This variant has been previously reported as a homozygous and a compound heterozygous change in patients with Mitochondriopathy with optic atrophy (PMID: 29040572, 33348459). Functional studies in patient fibroblasts indicate that the p.Arg429Trp variant decreases FDXR protein levels, and in vitro studies demonstrate that the variant leads to mitochondrial dysfunction (PMID: 29040572). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.02% (45/250556) and thus is presumed to be rare. The c.1285C>T (p.Arg429Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1285C>T (p.Arg429Trp) variant is classified as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV003411472 SCV004116030 likely pathogenic FDXR-related disorder 2023-03-08 criteria provided, single submitter clinical testing The FDXR c.1156C>T variant is predicted to result in the amino acid substitution p.Arg386Trp. This variant has been reported as pathogenic for autosomal recessive mitochondriopathy with optic atrophy (seven homozygotes and one compound heterozygote from six unrelated families), representing 42% (11 of 26) of pathogenic variants identified in this study (described as p.R392W, Peng et al. 2017. PubMed ID: 29040572). This variant was also reported in the homozygous state in two additional patients from unrelated families with features consistent with FDXR-related disease, and was reported to result in a moderately severe phenotype in comparison to other homozygous pathogenic variants (Stenton. 2021. PubMed ID: 33348459; described as p.Arg392Trp, O'Brien et al. 2021. PubMed ID: 34906498). Functional studies found this variant led to deficient ferredoxin NADP reductase activity and mitochondrial dysfunction in patient fibroblasts (Peng et al. 2017. PubMed ID: 29040572). This variant is reported in 0.13% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-72860036-G-A). In ClinVar this variant is listed as pathogenic (2) and likely pathogenic (1) by other clinical laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/520994/). We interpret this variant as likely pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV002470935 SCV005918003 pathogenic Auditory neuropathy-optic atrophy syndrome 2023-10-16 criteria provided, single submitter research
OMIM RCV004595518 SCV005077932 pathogenic Multiple mitochondrial dysfunctions syndrome 9b 2024-07-16 no assertion criteria provided literature only

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