Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000622739 | SCV000740748 | likely pathogenic | Inborn genetic diseases | 2022-07-05 | criteria provided, single submitter | clinical testing | The c.202G>C (p.D68H) alteration is located in exon 2 of the COQ4 gene. This alteration results from a G to C substitution at nucleotide position 202, causing the aspartic acid (D) at amino acid position 68 to be replaced by a histidine (H). Based on data from gnomAD, the C allele has an overall frequency of <0.01% (10/239964) total alleles studied. The highest observed frequency was 0.02% (1/6244) of Other alleles. This alteration has been detected in conjunction with a pathogenic COQ4 alteration in multiple individuals with COQ4-related primary coenzyme Q deficiency (Chung, 2015; Barbosa-Gouveia, 2021). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. |
| Invitae | RCV000258061 | SCV000775142 | pathogenic | Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome | 2023-09-19 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 267347). This missense change has been observed in individual(s) with clinical features of coenzyme Q10 deficiency and/or multiple congenital anomalies (PMID: 26185144, 26795593, 27513193, 32718099). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs758522459, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 68 of the COQ4 protein (p.Asp68His). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000258061 | SCV004021135 | likely pathogenic | Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome | 2023-06-02 | criteria provided, single submitter | clinical testing | Variant summary: COQ4 c.202G>C (p.Asp68His) results in a non-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. In addition, this variant is located at the last nucleotide of exon 2, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 5' donor site, and one predicts the variant has no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.3e-05 in 208574 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.202G>C has been reported in the literature in several compound heterozygous individuals, including two siblings, affected with Neonatal Encephalomyopathy-Cardiomyopathy Distress Syndrome (e.g., Chung_2015, Helbig_2016, Farwell-Hagman_2017, deCastro_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26185144, 27513193, 26795593, 32718099). Three ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as pathogenic (n = 2) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| OMIM | RCV000258061 | SCV000328228 | pathogenic | Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome | 2016-10-27 | no assertion criteria provided | literature only |