Submissions for variant NM_025152.3(NUBPL):c.166G>A (p.Gly56Arg)

gnomAD frequency: 0.00017  dbSNP: rs200401432

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196589	SCV000251971	uncertain significance	not provided	2020-06-21	criteria provided, single submitter	clinical testing	Reported previously as a pathogenic variant in individuals with mitochondrial complex I deficiency who also harbored a splice variant on the same NUBPL allele (in cis) and another sequence change on the opposite NUBPL allele (Calvo et al., 2010; Tucker et al., 2012; Kevelam et al., 2013).; Functional analysis found this variant does not complex I assembly or function (Calvo et al., 2010; Kevelam et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32518176, 23553477, 20818383, 23828044, 22072591, 31787496)
Ambry Genetics	RCV000622708	SCV000742093	likely pathogenic	Inborn genetic diseases	2021-04-13	criteria provided, single submitter	clinical testing	The c.166G>A (p.G56R) alteration is located in coding exon 2 of the NUBPL gene. This alteration results from a G to A substitution at nucleotide position 166, causing the glycine (G) at amino acid position 56 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD) database, the NUBPL p.G56R (c.166G>A) alteration was observed in 0.01% (41/280362) of total alleles studied (including 1 homozygote), with a frequency of 0.03% (39/128288) in the European (non-Finnish) subpopulation. The [c.166G>A (p.G56R); c.815-27T>C] complex allele has been reported in the homozygous state, compound heterozygous state, and confirmed in trans with a second pathogenic allele in multiple unrelated patients with mitochondrial encephalomyopathy (Calvo, 2010; Kevelam, 2013). Emerging evidence is suggestive that the NUBPL [c.166G>A (p.G56R); c.815-27T>C] complex allele is likely pathogenic when these alterations are in cis; however, the clinical significance of these alterations in isolation remains uncertain. The p.G56 amino acid is highly conserved in available vertebrate species. Functional analysis of cultured fibroblasts from a patient bearing the [c.166G>A (p.G56R); c.815-27T>C] complex allele in trans with a complex rearrangement, as well as a control patient who was heterozygous for only the c.815-27T>C alteration, demonstrated an aberrant RT-PCR pattern with three distinct transcripts: wild-type, a lengthened transcript resulting from a cryptic splice site which introduces an additional 72 bp and results in a frameshift (p.G272Vfs*11), as well as a truncated transcript generated due to exon 10 skipping resulting in a frameshift (p.D273Qfs*31) (Tucker, 2012). Analysis by qRT-PCR and Western blot showed that the heterozygous control with only the c.815-27T>C alteration had reduced mRNA expression (74%) and protein expression (59%) compared to wild type controls, and the patient with the [c.166G>A (p.G56R); c.815-27T>C] complex allele and complex rearrangement on the other allele had more significant reduction in mRNA expression (15%) and undetectable protein expression (Tucker, 2012). No defective function was identified when the protein with the G56R missense change was over-expressed (Tucker, 2012). The p.D273Qfs*31 transcript is completely non-functional in yeast assays (Wydro, 2013; Maclean, 2018). The p.G56R alteration is predicted to be tolerated by protein in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Undiagnosed Diseases Network, NIH	RCV001526454	SCV001736868	uncertain significance	Mitochondrial complex 1 deficiency, nuclear type 21	2020-08-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196589	SCV003255705	uncertain significance	not provided	2022-07-05	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 214885). This missense change has been observed in individual(s) with mitochondrial complex I deficiency. In all cases this variant has been reported to occur on the same chromosome (in cis) with c.815-27T>C. (PMID: 20818383, 22072591, 23553477, 32518176). This variant is present in population databases (rs200401432, gnomAD 0.03%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 56 of the NUBPL protein (p.Gly56Arg).