Submissions for variant NM_001358921.2(COQ2):c.533A>G (p.Asn178Ser)

gnomAD frequency: 0.00009  dbSNP: rs121918232

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000001504	SCV001164363	uncertain significance	Coenzyme Q10 deficiency, primary, 1	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Asn228Ser variant in COQ2 was identified by our study in the compound heterozygous state, along with another VUS, in one individual with primary coenzyme q10 deficiency. The p.Asn228Ser variant in COQ2 has been reported in 1 Eastern European individual withprimary coenzyme q10 deficiency (PMID: 17855635), and has been identified in 0.02376% (30/126254) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121918232). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The presence of this variant in combination with a variant reported pathogenic by OMIM in ClinVar and in an individual with primary coenzyme q10 deficiency slightly increases the likelihood that the p.Asn228Ser variant is pathogenic (PMID: 17855635; Variation ID: 1438). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PM3_Supporting (Richards 2015).
GeneDx	RCV001753396	SCV002006889	likely pathogenic	not provided	2024-06-28	criteria provided, single submitter	clinical testing	Observed multiple times with another COQ2 variant in patients with childhood-onset renal disease in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 29127259, 29637272, 30295827); Published functional studies in yeast suggest a damaging effect: decreased CoQ content compared to wild type (PMID: 27493029); 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: 20495179, 25373618, 31660881, 30295827, 29127259, 29637272, 33426503, 23343605, 27493029, 17855635, 18235438, 23349334, 36420660, 20689595, 35483523, 36266294, 29869118, 38774208, 37734845)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001753396	SCV002230810	uncertain significance	not provided	2022-08-15	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 228 of the COQ2 protein (p.Asn228Ser). This variant is present in population databases (rs121918232, gnomAD 0.02%). This missense change has been observed in individual(s) with COQ2-related steroid-resistant nephrotic syndrome (PMID: 17855635, 23349334, 29127259, 29637272, 29869118, 30295827). ClinVar contains an entry for this variant (Variation ID: 1439). 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 tolerated. Experimental studies have shown that this missense change affects COQ2 function (PMID: 17855635, 20689595). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001504	SCV002600343	pathogenic	Coenzyme Q10 deficiency, primary, 1	2022-10-07	criteria provided, single submitter	clinical testing	Variant summary: COQ2 c.683A>G (p.Asn228Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 248218 control chromosomes. This frequency does not allow conclusions about variant significance. c.683A>G has been reported in the literature as biallelic compound heterozygous or homozygous genotypes in multiple comprehensively genotyped (WES or large NGS panel based analysis) individuals affected with Coenzyme Q10 Deficiency, Primary, 1 (example, Dimedl-Camassei_2007, McCarthy_2013, Sadowski_2015, Shapiro_2019, Warejko_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported although individuals with compound heterozygous genotypes have been reported with biochemical analyses demonstrating decreased activities of respiratory chain complexes (II + III) and decreased CoQ10 levels in the skeletal muscle and renal cortex, findings consistent with the pathophysiology of disease (Dimedl-Camassei_2007, Lopez_2010). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=2; Likely pathogenic, n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002512649	SCV003699757	likely pathogenic	Inborn genetic diseases	2021-04-15	criteria provided, single submitter	clinical testing	The c.683A>G (p.N228S) alteration is located in exon 3 (coding exon 3) of the COQ2 gene. This alteration results from an A to G substitution at nucleotide position 683, causing the asparagine (N) at amino acid position 228 to be replaced by a serine (S). Based on data from the Genome Aggregation Database (gnomAD) database, the COQ2 c.683A>G alteration was observed in 0.01% (32/279612) of total alleles studied, with a frequency of 0.02% (29/127994) in the non-Finnish European subpopulation. This alteration has been reported in the homozygous or compound heterozygous state with other COQ2 variants in multiple individuals with steroid-resistant nephrotic syndrome (Diomedi-Camassei, 2007; McCarthy, 2013; Sadowski, 2015; Bezdíka, 2018; Warejko, 2018; Starr, 2018; Schapiro, 2019). This amino acid position is completely conserved on sequence alignment. Studies of patient skin fibroblasts with this alteration showed decreased CoQ10 levels, decreased ATP, increased protein oxidation, and cell death, while studies in a yeast model demonstrated decreased CoQ6 production (described as N178S/p.Asn178Ser due to alternate nomenclature) (Quinzii, 2010; Desbats, 2016). The in silico prediction for the p.N228S alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
OMIM	RCV000001504	SCV000021659	pathogenic	Coenzyme Q10 deficiency, primary, 1	2007-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000416407	SCV000494123	not provided	Coenzyme Q10 deficiency		no assertion provided	literature only
Yale Center for Mendelian Genomics, Yale University	RCV001849251	SCV002106636	likely pathogenic	Nephrotic syndrome	2017-11-10	no assertion criteria provided	literature only