Submissions for variant NM_024876.4(COQ8B):c.532C>T (p.Arg178Trp)

gnomAD frequency: 0.00004  dbSNP: rs398122978

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000077753	SCV001520809	pathogenic	Nephrotic syndrome, type 9	2023-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001701490	SCV001986371	uncertain significance	not provided	2020-03-05	criteria provided, single submitter	clinical testing	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: 24270420, 32859164, 31130284, 31937884, 29194833, 29382012, 28454995, 32543055)
Revvity Omics, Revvity	RCV000077753	SCV002019709	pathogenic	Nephrotic syndrome, type 9	2021-05-12	criteria provided, single submitter	clinical testing
Invitae	RCV001701490	SCV003443913	likely pathogenic	not provided	2022-03-21	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with steroid-resistant nephrotic syndrome (PMID: 24270420, 28204945, 28454995, 29382012, 31130284, 31937884, 32543055, 32604935, 32859164). It has also been observed to segregate with disease in related individuals. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects COQ8B function (PMID: 29194833). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COQ8B protein function. ClinVar contains an entry for this variant (Variation ID: 91845). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 178 of the COQ8B protein (p.Arg178Trp).
Precision Medicine Center, Zhengzhou University	RCV000077753	SCV004218435	pathogenic	Nephrotic syndrome, type 9	2023-12-01	criteria provided, single submitter	clinical testing	PM2_p,PM3_strong,PP3
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000077753	SCV004804794	pathogenic	Nephrotic syndrome, type 9	2024-03-17	criteria provided, single submitter	research
Ambry Genetics	RCV004019521	SCV004850475	likely pathogenic	Inborn genetic diseases	2023-11-03	criteria provided, single submitter	clinical testing	The c.532C>T (p.R178W) alteration is located in exon 7 (coding exon 6) of the COQ8B gene. This alteration results from a C to T substitution at nucleotide position 532, causing the arginine (R) at amino acid position 178 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.003% (7/279154) total alleles studied. The highest observed frequency was 0.02% (4/19808) of East Asian alleles. This alteration was detected in the homozygous state in multiple individuals with COQ8B-related primary coenzyme Q10 deficiency (Al-Hamed, 2022; Alvi, 2022; Maeoka, 2020; Ashraf, 2013). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
OMIM	RCV000077753	SCV000109559	pathogenic	Nephrotic syndrome, type 9	2013-12-02	no assertion criteria provided	literature only
GeneReviews	RCV000077753	SCV000494108	not provided	Nephrotic syndrome, type 9		no assertion provided	literature only
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000077753	SCV000863832	pathogenic	Nephrotic syndrome, type 9	2018-03-13	no assertion criteria provided	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000077753	SCV001133137	likely pathogenic	Nephrotic syndrome, type 9	2019-09-26	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701490	SCV001932756	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001701490	SCV001951053	likely pathogenic	not provided		no assertion criteria provided	clinical testing