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.
ClinVar Genomic variation as it relates to human health
NM_024876.4(COQ8B):c.532C>T (p.Arg178Trp)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(13)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
13
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_024876.4(COQ8B):c.532C>T (p.Arg178Trp)
Variation ID: 91845 Accession: VCV000091845.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19q13.2 19: 40705140 (GRCh38) [ NCBI UCSC ] 19: 41211045 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 10, 2016 Sep 29, 2024 Mar 18, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024876.4:c.532C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_079152.3:p.Arg178Trp missense NM_001142555.3:c.409C>T NP_001136027.1:p.Arg137Trp missense NC_000019.10:g.40705140G>A NC_000019.9:g.41211045G>A NG_027800.1:g.16746C>T Q96D53:p.Arg178Trp - Protein change
- R178W, R137W
- Other names
- -
- Canonical SPDI
- NC_000019.10:40705139:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| COQ8B | - | - |
GRCh38 GRCh37 |
264 | 275 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Mar 17, 2024 | RCV000077753.23 | |
| Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 18, 2024 | RCV001701490.17 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Nov 3, 2023 | RCV004019521.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Feb 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Nephrotic syndrome, type 9
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001520809.2
First in ClinVar: Mar 22, 2021 Last updated: Oct 06, 2023 |
|
|
|
Pathogenic
(May 12, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Nephrotic syndrome, type 9
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019709.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Likely pathogenic
(Nov 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV004850475.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Likely pathogenic
(Mar 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001986371.3
First in ClinVar: Nov 06, 2021 Last updated: Sep 29, 2024 |
Comment:
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: 31130284, … (more)
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: 31130284, 29194833, 29382012, 28454995, 36177613, 32859164, 31328266, 34605136, 35483523, 36176665, 35755072, 37217505, 33677064, 36532926, AlsanieW2022[Article], WangY2024[Review], 35683636, 36898413, 36843884, 36034551, 28204945, 35046417, 34638552, 33413146, 32543055, 24270420, 32604935, 31937884) (less)
|
|
|
Pathogenic
(Dec 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Nephrotic syndrome, type 9
Affected status: yes
Allele origin:
paternal
|
Precision Medicine Center, Zhengzhou University
Accession: SCV004218435.1
First in ClinVar: Jun 23, 2024 Last updated: Jun 23, 2024 |
Comment:
PM2_p,PM3_strong,PP3
Sex: male
|
|
|
Likely pathogenic
(Mar 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003443913.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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). (less)
|
|
|
Pathogenic
(Mar 17, 2024)
|
criteria provided, single submitter
Method: research
|
Nephrotic syndrome, type 9
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804794.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(Dec 02, 2013)
|
no assertion criteria provided
Method: literature only
|
NEPHROTIC SYNDROME, TYPE 9
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000109559.2
First in ClinVar: Dec 25, 2013 Last updated: Nov 10, 2016 |
Comment on evidence:
In 2 sibs, born of consanguineous Arab parents, with nephrotic syndrome type 9 (NPHS9; 615573), Ashraf et al. (2013) identified a homozygous c.532C-T transition in … (more)
In 2 sibs, born of consanguineous Arab parents, with nephrotic syndrome type 9 (NPHS9; 615573), Ashraf et al. (2013) identified a homozygous c.532C-T transition in exon 7 of the ADCK4 gene, resulting in an arg178-to-trp (R178W) substitution at a highly conserved residue. The mutation was found by homozygosity mapping combined with whole-exome sequencing and segregated with the disorder in the family. It was not present in over 190 ethnically matched controls or in the Exome Variant Server database. Functional studies were not performed. The patients had onset of steroid-resistant nephrotic syndrome at ages 7 and 13 years, respectively, and underwent renal transplantation at ages 10 and 15 years, respectively. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001932756.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951053.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(Mar 13, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Nephrotic syndrome, type 9
Affected status: yes
Allele origin:
germline
|
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV000863832.1
First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018 |
|
|
|
Likely pathogenic
(Sep 26, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Nephrotic syndrome, type 9
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001133137.1
First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Nephrotic syndrome, type 9
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000494108.2
First in ClinVar: Nov 10, 2016 Last updated: Oct 01, 2022 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
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: 31130284, 29194833, 29382012, 28454995, 36177613, 32859164, 31328266, 34605136, 35483523, 36176665, 35755072, 37217505, 33677064, 36532926, AlsanieW2022[Article], WangY2024[Review], 35683636, 36898413, 36843884, 36034551, 28204945, 35046417, 34638552, 33413146, 32543055, 24270420, 32604935, 31937884)
Comment:
PM2_p,PM3_strong,PP3
Comment:
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).
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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: 31130284, 29194833, 29382012, 28454995, 36177613, 32859164, 31328266, 34605136, 35483523, 36176665, 35755072, 37217505, 33677064, 36532926, AlsanieW2022[Article], WangY2024[Review], 35683636, 36898413, 36843884, 36034551, 28204945, 35046417, 34638552, 33413146, 32543055, 24270420, 32604935, 31937884)
Comment:
PM2_p,PM3_strong,PP3
Comment:
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).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Primary Coenzyme Q(10) Deficiency Overview. | Adam MP | - | 2023 | PMID: 28125198 |
| COQ8B-Related Steroid-Resistant Nephrotic Syndrome in Saudi Arabia: A Case Report. | Alvi NH | Cureus | 2022 | PMID: 36532926 |
| Exome sequencing unravels genetic variants associated with chronic kidney disease in Saudi Arabian patients. | Al-Hamed MH | Human mutation | 2022 | PMID: 36177613 |
| A case report of adult-onset COQ8B nephropathy presenting focal segmental glomerulosclerosis with granular swollen podocytes. | Maeoka Y | BMC nephrology | 2020 | PMID: 32859164 |
| Genetic Study in Korean Pediatric Patients with Steroid-Resistant Nephrotic Syndrome or Focal Segmental Glomerulosclerosis. | Park E | Journal of clinical medicine | 2020 | PMID: 32604935 |
| COQ8B nephropathy: Early detection and optimal treatment. | Song X | Molecular genetics & genomic medicine | 2020 | PMID: 32543055 |
| Comprehensive genetic diagnosis of Japanese patients with severe proteinuria. | Nagano C | Scientific reports | 2020 | PMID: 31937884 |
| Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. | Monies D | American journal of human genetics | 2019 | PMID: 31130284 |
| Mutations in COQ8B (ADCK4) found in patients with steroid-resistant nephrotic syndrome alter COQ8B function. | Vazquez Fonseca L | Human mutation | 2018 | PMID: 29194833 |
| Coenzyme Q10 supplementation therapy for 2 children with proteinuria renal disease and ADCK4 mutation: Case reports and literature review. | Feng C | Medicine | 2017 | PMID: 29382012 |
| A multicenter clinical exome study in unselected cohorts from a consanguineous population of Saudi Arabia demonstrated a high diagnostic yield. | Alfares A | Molecular genetics and metabolism | 2017 | PMID: 28454995 |
| Spectrum of mutations in Chinese children with steroid-resistant nephrotic syndrome. | Wang F | Pediatric nephrology (Berlin, Germany) | 2017 | PMID: 28204945 |
| Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
| ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. | Ashraf S | The Journal of clinical investigation | 2013 | PMID: 24270420 |
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Text-mined citations for rs398122978 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.