ClinVar Miner

Submissions for variant NM_174889.5(NDUFAF2):c.139C>T (p.Arg47Ter) (rs137852863)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624428 SCV000740741 pathogenic Inborn genetic diseases 2014-09-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV000679870 SCV000807244 pathogenic Leigh syndrome 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 4-month-old female with cutis marmorata telangiectasia congenita, onset of nystagmus and poor suck at 3.5 months, normal MRI, but with a brother deceased from Leigh syndrome with similar symptom onset
Illumina Clinical Services Laboratory,Illumina RCV000779476 SCV000916105 likely pathogenic Mitochondrial complex I deficiency, nuclear type 1 2018-09-17 criteria provided, single submitter clinical testing The NDUFAF2 c.139C>T (p.Arg47Ter) variant, also known as c.182C>T (p.Arg45Ter), is a stop-gained variant predicted to result in premature termination of the protein. The variant has been reported in two studies in which it is found in two individuals. Ogilvie et al. (2005) reported a proband with an atypical phenotype of leukoencephalopathy with vanishing white matter, who was a hemizygote for the c.139C>T (p.Arg47Ter) variant. The proband inherited the p.Arg47Ter variant from her unaffected mother, and inherited a deletion variant from her unaffected father. Helbig et al. (2016) identified the p.Arg47Ter variant in a homozygous state in one proband with epileptic encephalopathy. Control data are unavailable for the p.Arg47Ter variant, which is reported at a frequency of 0.000265 in the East Asian population of the Genome Aggregation Database. Functional studies in proband fibroblasts demonstrated that wildtype NDUFAF2 transduction restored the complex I deficiency and activity to control levels, indicating the p.Arg47Ter variant was responsible for the proband's phenotype (Ogilvie et al. 2005). Based on the evidence, the p.Arg47Ter variant is classified as likely pathogenic for mitochondrial respiratory chain complex I deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000781647 SCV000919858 pathogenic not specified 2018-02-08 criteria provided, single submitter clinical testing Variant summary: NDUFAF2 c.139C>T (p.Arg47X) 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 have been classified as pathogenic by our laboratory (e.g., p.Trp74X). The variant allele was found at a frequency of 4.3e-05 in 276654 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in NDUFAF2 causing Leigh Syndrome (4.3e-05 vs 0.0013), allowing no conclusion about variant significance. The c.139C>T variant has been reported in the literature in multiple individuals affected with Leigh Syndrome. This data indicates that the variant may be associated with disease. At least one publication reports experimental evidence showing a lack of mature protein and no catalytic activity of the mitochondrial complex I (Ogilvie_2005). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000001661 SCV000021817 pathogenic Mitochondrial complex 1 deficiency, nuclear type 10 2005-10-01 no assertion criteria provided literature only

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