Submissions for variant NM_002491.3(NDUFB3):c.208G>T (p.Gly70Ter)

gnomAD frequency: 0.00016  dbSNP: rs200800978

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000412836	SCV000490663	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, specifically expression of NDUFB3 cDNA with either the p.W22R or p.G70X variants failed to rescue the complex I deficiency in patient fibroblasts (Haack et al., 2012); Nonsense variant predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 33233646, 26795593, 31589614, 22499348)
Ambry Genetics	RCV000624112	SCV000740858	pathogenic	Inborn genetic diseases	2015-03-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000033057	SCV002018240	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 25	2019-12-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000412836	SCV002064347	likely pathogenic	not provided	2019-07-02	criteria provided, single submitter	clinical testing	DNA sequence analysis of the NDUFB3 gene demonstrated a sequence change, c.208G>T, which results in the creation of a premature stop codon at amino acid position 70, p.Gly70*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated NDUFB3 protein with potentially abnormal function. This sequence change has previously been described in a patient with isolated complex I deficiency along with another missense variant in this gene, and functional studies were performed to demonstrate pathogenicity (Haack et al., 2012). The phenotypic presentation included mitochondrial encephalopathy, mitochondrial myopathy, muscular hypotonia, developmental delay and lactic acidosis. These collective evidences indicate that this sequence change is likely pathogenic.
Invitae	RCV000412836	SCV002283147	uncertain significance	not provided	2022-07-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly70*) in the NDUFB3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the NDUFB3 protein. This variant is present in population databases (rs200800978, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 22499348, 26795593). ClinVar contains an entry for this variant (Variation ID: 39836). Studies have shown that this premature translational stop signal alters NDUFB3 gene expression (PMID: 22499348). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM	RCV000033057	SCV000056837	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 25	2012-04-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000412836	SCV001551879	likely pathogenic	not provided		no assertion criteria provided	clinical testing	The NDUFB3 p.Gly70* variant was identified as a compound heterozygous variant in individuals with mitochondrial complex I deficiency; functional studies in fibroblasts from this patient demonstrated low complex I activity (Haack_2012_PMID:22499348). The variant was identified in dbSNP (ID: rs200800978) and ClinVar (classified as likely pathogenic by GeneDx and as pathogenic by Ambry Genetics). The variant was identified in control databases in 31 of 282238 chromosomes at a frequency of 0.0001098 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 24 of 128702 chromosomes (freq: 0.000187), Latino in 5 of 35410 chromosomes (freq: 0.000141), Other in 1 of 7204 chromosomes (freq: 0.000139) and South Asian in 1 of 30608 chromosomes (freq: 0.000033), but was not observed in the African, Ashkenazi Jewish, East Asian, or European (Finnish) populations. The c.208G>T variant leads to a premature stop codon at position 70, which is predicted to lead to a truncated or absent protein and loss of function in homozygous individuals. Loss of function variants in the NDUFB3 gene are an established mechanism of disease for mitochondrial complex I deficiency and are the type of variant expected to cause the disorder when found in homozygous or compound heterozygous individuals. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.