ClinVar Miner

Submissions for variant NM_174889.5(NDUFAF2):c.114C>G (p.Tyr38Ter) (rs199754807)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485122 SCV000566903 pathogenic not provided 2015-06-18 criteria provided, single submitter clinical testing The Y38X nonsense variant in the NDUFAF2 gene has been reported previously in association with mitochondrial complex I deficiency (Hoefs et al. 2009). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we interpret Y38X as a pathogenic variant.
Counsyl RCV000674200 SCV000799498 uncertain significance Cockayne syndrome type A 2018-04-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780529 SCV000917864 pathogenic not specified 2018-11-21 criteria provided, single submitter clinical testing Variant summary: NDUFAF2 c.114C>G (p.Tyr38X) 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. Truncations downstream of this position has been classified as pathogenic by our laboratory (e.g. c.139C>T, p.Arg47X; c.221G>A, p.Trp74X). The variant allele was found at a frequency of 5.4e-05 in 277122 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in NDUFAF2 causing Leigh Syndrome (5.4e-05 vs 0.0013), allowing no conclusion about variant significance. The variant, c.114C>G, has been reported in the literature in one homozygote individual affected with Leigh Syndrome (Hoefs_2009). These data indicate that the variant may be associated with disease. The same publication reports experimental evidence showing no NDUFAF2 protein expression in patient's fibroblasts and a marked decrease in complex I activity (to 21-23% of the lowest control value). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic x2, VUS x1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000590864 SCV000700072 pathogenic Mitochondrial complex 1 deficiency, nuclear type 10 2018-12-13 no assertion criteria provided literature only

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