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

gnomAD frequency: 0.00004  dbSNP: rs137852863

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000624428	SCV000740741	pathogenic	Inborn genetic diseases	2014-10-08	criteria provided, single submitter	clinical testing	The c.139C>T (p.R47*) alteration, located in coding exon 2 (c.128_217) of the NDUFAF2 gene, consists of a C to T substitution at nucleotide position 139. This changes the amino acid from an Arginine (R) to a stop codon within coding exon 2 (c.128_217). Premature stop codons are typically deleterious in nature (Richards, 2008). The alteration has been observed in affected individuals: Homozygous c.139C>T (p.R47*) alterations have been reported in a non-consanguineous female patient of Chinese, Portuguese, and Jewish descent with complex I deficiency and clinical features overlapping with the proband including respiratory failure, global developmental delays, and brain MRI findings consistent with Leigh syndrome (Ogilvie, 2005). Based on the available evidence, this alteration is classified as pathogenic.
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 Laboratory Services, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
GeneDx	RCV001582459	SCV001817963	pathogenic	not provided	2022-06-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that this variant causes a severe reduction in complex I activity and levels of holoenzyme (Ogilvie et al., 2005); 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; Also denoted as R45X due to alternate nomenclature; This variant is associated with the following publications: (PMID: 25525159, 25326635, 16200211, 10649489, 26795593, 31130284, 34503567)
Invitae	RCV001582459	SCV003525827	pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg47*) in the NDUFAF2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NDUFAF2 are known to be pathogenic (PMID: 18180188). This variant is present in population databases (rs137852863, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with clinical features of NDUFAF2-related conditions (PMID: 16200211, 31130284). This variant is also known as R45X. ClinVar contains an entry for this variant (Variation ID: 1594). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000001661	SCV000021817	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 10	2005-10-01	no assertion criteria provided	literature only