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

gnomAD frequency: 0.00003  dbSNP: rs199754807

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485122	SCV000566903	pathogenic	not provided	2023-05-26	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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19384974)
Counsyl	RCV000674200	SCV000799498	uncertain significance	Cockayne syndrome type 1	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]
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000590864	SCV002557530	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 10	2020-05-21	criteria provided, single submitter	clinical testing	A heterozygous nonsense variant, NM_174889.4(NDUFAF2):c.114C>G, has been identified in exon 1 of 4 of the NDUFAF2 gene. The variant is predicted to result in a premature stop codon at position 38 of the protein, NP_777549.1(NDUFAF2):p.(Tyr38*). This variant is predicted to result in loss of protein function through truncation (including the NDUFA12 domain), which is a reported mechanism of pathogenicity for this gene. The variant has been previously described as pathogenic and identified in a homozygous patient with complex I deficiency and clinical symptoms of Leigh disease (ClinVar, Hoefs, S. et al. (2009)). Additionally, functional studies showed a decrease in complex I activity in the cultured skin fibroblasts and a disturbance in the assembly of complex I (Hoefs, S. et al. (2009)). Other variants resulting in a truncated protein have been reported as pathogenic in this gene (ClinVar)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Invitae	RCV000485122	SCV004291832	pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr38*) 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 (rs199754807, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 19384974). ClinVar contains an entry for this variant (Variation ID: 419231). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590864	SCV004563745	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 10	2023-08-28	criteria provided, single submitter	clinical testing	The NDUFAF2 c.114C>G; p.Tyr38Ter variant (rs199754807) is reported in the literature in a homozygous individual affected with mitochondrial complex I deficiency (Hoefs 2009). This variant is reported in ClinVar (Variation ID: 419231) and is found in the general population with an overall allele frequency of 0.005% (15/282,774 alleles) in the Genome Aggregation Database (v2.1.1). This variant induces an early termination codon and while mRNA studies of patient cells suggest this variant may escape nonsense-mediated decay, it is predicted to result in a truncated protein. Patient cells homozygous for this variant exhibit significantly decreased mitochondrial complex I activity (Hoefs 2009). Based on available information, this variant is considered to be pathogenic. References: Hoefs SJ et al. Baculovirus complementation restores a novel NDUFAF2 mutation causing complex I deficiency. Hum Mutat. 2009 Jul;30(7):E728-36. PMID: 19384974.
OMIM	RCV000590864	SCV000700072	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 10	2018-12-13	no assertion criteria provided	literature only