Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000509578 | SCV000967588 | likely pathogenic | Auditory neuropathy-optic atrophy syndrome | 2018-12-26 | criteria provided, single submitter | clinical testing | The p.Arg337Cys variant in FDXR (also known as p.Arg306Cys) has been reported in 1 homozygous individual and 1 compound heterozygous individual with auditory n europathy and optic atrophy (Paul 2017). The variant segregated with disease in 3 relatives (Paul 2017). In vivo functional studies in yeast provide some eviden ce that the p.Arg337Cys variant may impact protein function (Paul 2017). However , these types of assays may not accurately represent biological function. This v ariant has been identified in 3/34332 Latino and 4/107544 European chromosomes b y the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Co mputational prediction tools and conservation analysis do not provide strong sup port for or against an impact to the protein. In summary, although additional st udies are required to fully establish its clinical significance, the p.Arg337Cys variant is likely pathogenic. ACMG/AMP criteria applied: PP1_Strong, PM2, PM3, PS3_Supporting. |
| Ambry Genetics | RCV002527390 | SCV003705825 | likely pathogenic | Inborn genetic diseases | 2022-09-06 | criteria provided, single submitter | clinical testing | The c.934C>T (p.R312C) alteration is located in exon 9 (coding exon 9) of the FDXR gene. This alteration results from a C to T substitution at nucleotide position 934, causing the arginine (R) at amino acid position 312 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of <0.01% (7/241968) total alleles studied. The highest observed frequency was 0.01% (3/34332) of Latino alleles. This alteration was detected in conjunction with another pathogenic FDXR mutation in an individual with bilateral auditory neuropathy, adolescent-onset hearing defects, and bilateral optic atrophy. In addition, this alteration was detected in the homozygous state and segregated with disease among multiple individuals in one family who had clinical features consistent with FDXR-related mitochondrial encephalomyopathy (Paul, 2017). This amino acid position is well conserved in available vertebrate species. Functional assays in patient fibroblasts show aberrant ferredoxin reductase levels, respiratory chain enzyme activity, and iron uptake (Paul, 2017). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. |
| OMIM | RCV000509578 | SCV000607716 | pathogenic | Auditory neuropathy-optic atrophy syndrome | 2017-10-12 | no assertion criteria provided | literature only |