ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485122 SCV000566903 pathogenic not provided 2021-08-28 criteria provided, single submitter clinical testing Nonsense 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; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19384974)
Counsyl RCV000674200 SCV000799498 uncertain significance Cockayne syndrome type A 2018-04-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Baylor Genetics RCV001335554 SCV001528725 pathogenic Mitochondrial complex I deficiency, nuclear type 1 2018-12-12 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing [PMID 19384974]
OMIM RCV000590864 SCV000700072 pathogenic Mitochondrial complex 1 deficiency, nuclear type 10 2018-12-13 no assertion criteria provided literature only

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