Submissions for variant NM_016035.5(COQ4):c.718C>T (p.Arg240Cys)

gnomAD frequency: 0.00017  dbSNP: rs143441644

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000256139	SCV000321520	pathogenic	not provided	2022-11-10	criteria provided, single submitter	clinical testing	Functional studies find that p.(R240C) significantly impairs oxidative growth in a recombinant yeast model (Brea-Calvo G et al., 2015).; 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: 26185144, 25658047, 28540186, 33704555, 34440436, 31589614, 32746448, 33726816, 31967322, 29255295, 32718099, 30642647)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000169636	SCV000680182	pathogenic	Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome	2017-10-19	criteria provided, single submitter	clinical testing
Invitae	RCV000169636	SCV000828752	pathogenic	Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 240 of the COQ4 protein (p.Arg240Cys). This variant is present in population databases (rs143441644, gnomAD 0.3%). This missense change has been observed in individual(s) with COQ4-related conditions (PMID: 25658047, 26185144, 32718099, 33704555). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 189201). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COQ4 protein function. Experimental studies have shown that this missense change affects COQ4 function (PMID: 26185144, 33704555). For these reasons, this variant has been classified as Pathogenic.
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV001640262	SCV001519121	pathogenic	Spastic ataxia	2021-01-04	criteria provided, single submitter	research
New York Genome Center	RCV000169636	SCV002564361	likely pathogenic	Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome	2021-08-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169636	SCV002816427	likely pathogenic	Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome	2021-09-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002515203	SCV003758080	pathogenic	Inborn genetic diseases	2022-05-05	criteria provided, single submitter	clinical testing	The c.718C>T (p.R240C) alteration is located in exon 7 (coding exon 7) of the COQ4 gene. This alteration results from a C to T substitution at nucleotide position 718, causing the arginine (R) at amino acid position 240 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.02% (50/278786) total alleles studied. The highest observed frequency was 0.34% (35/10230) of Ashkenazi Jewish alleles. This alteration has been detected in the homozygous state and in trans with other pathogenic COQ4 alterations in multiple individuals with COQ4-related primary coenzyme Q10 deficiency (Brea-Calvo, 2015; Chung, 2015; de Castro, 2020; Galatolo, 2021; Mero, 2021; Barbosa-Gouveia, 2021). This amino acid position is highly conserved in available vertebrate species. In functional studies involving a recombinant yeast model, human COQ4 with the R240C variant was unable to rescue loss of yeast COQ4 (Brea-Calvo, 2015). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003390884	SCV004120574	pathogenic	COQ4-related disorder	2023-06-08	criteria provided, single submitter	clinical testing	The COQ4 c.718C>T variant is predicted to result in the amino acid substitution p.Arg240Cys. This variant was found in the homozygous and compound heterozygous state in multiple affected individuals with Coenzyme Q10 deficiency (see for example Brea-Calvo et al. 2015. PubMed ID: 25658047, Chung et al. 2015. PubMed ID: 26185144, de Castro et al. 2020. PubMed ID: 32718099). This variant is reported in 0.34% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-131095844-C-T). Functional characterization suggests that this variant has a deleterious effect on the protein (Brea-Calvo et al. 2015. PubMed ID: 25658047). This variant is interpreted as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000256139	SCV004227151	pathogenic	not provided	2023-03-29	criteria provided, single submitter	clinical testing	PP3, PM2_strong, PM3_strong, PS3, PS4_moderate
Revvity Omics, Revvity	RCV000169636	SCV004238555	likely pathogenic	Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome	2023-06-02	criteria provided, single submitter	clinical testing
OMIM	RCV000169636	SCV000221165	pathogenic	Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome	2015-02-05	no assertion criteria provided	literature only
GeneReviews	RCV000169636	SCV000494133	not provided	Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome		no assertion provided	literature only