VCV000091845.27 - ClinVar

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

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

8 out of 14 submissions contributed to this classification

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.

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: VCV000091845.27

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	Feb 15, 2026	Apr 14, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_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

... more HGVS ... less HGVS

Protein change

R178W, R137W

Other names

Canonical SPDI

NC_000019.10:40705139:G:A

Global minor allele frequency (GMAF) Help The 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.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Links

UniProtKB: Q96D53#VAR_070552 OMIM: 615567.0001 dbSNP: rs398122978 ClinGen: CA145471 VarSome

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
Gene	OMIM	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	331	342

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.
Nephrotic syndrome, type 9	Pathogenic/Likely pathogenic (9)	criteria provided, multiple submitters, no conflicts	Apr 14, 2025	RCV000077753.27
not provided	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Nov 14, 2024	RCV001701490.20
Inborn genetic diseases	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.	Expand all rows Collapse all rows 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) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Nephrotic syndrome, type 9	Baylor Genetics Accession: SCV001520809.2 First in ClinVar: Mar 22, 2021 Last updated: Oct 06, 2023	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely pathogenic (Nov 03, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Inborn genetic diseases	Ambry Genetics Accession: SCV004850475.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 24270420‚ 32859164‚ 36177613‚ 36532926 Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Mar 17, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Nephrotic syndrome, type 9	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre Accession: SCV004804794.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024	Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Likely pathogenic (Nov 14, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV001986371.4 First in ClinVar: Nov 06, 2021 Last updated: Jan 04, 2025	Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Dec 01, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Nephrotic syndrome, type 9	Precision Medicine Center, Zhengzhou University Accession: SCV004218435.2 First in ClinVar: Jun 23, 2024 Last updated: Apr 13, 2025	Publications: PubMed (2) PubMed: 24270420‚ 25741868 Comment: show PM2_p,PM3_strong,PP3 (less) Observation: 1 Collection method: clinical testing Allele origin: paternal Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: paternal Affected status: yes Sex: male

Pathogenic (May 12, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Nephrotic syndrome, type 9	Revvity Omics, Revvity Accession: SCV002019709.4 First in ClinVar: Nov 29, 2021 Last updated: Sep 06, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Apr 14, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Nephrotic syndrome, type 9	3billion Accession: SCV006581181.1 First in ClinVar: Oct 25, 2025 Last updated: Oct 25, 2025	Publications: PubMed (1) PubMed: 24270420 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Method: exome sequencing

Pathogenic (Nov 05, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003443913.4 First in ClinVar: Feb 07, 2023 Last updated: Feb 15, 2026	Publications: PubMed (11) PubMed: 24270420‚ 28204945‚ 28454995‚ 29194833‚ 29382012‚ 31130284‚ 31937884‚ 32543055‚ 32604935‚ 32859164‚ 34605136 Comment: show 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). 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 missense change has been observed in individuals with COQ8B-related conditions (PMID: 24270420, 28204945, 28454995, 29382012, 31130284, 31937884, 32543055, 32604935, 32859164, 34605136). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91845). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COQ8B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects COQ8B function (PMID: 29194833). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Dec 02, 2013) N Not contributing to aggregate classification	no assertion criteria provided	NEPHROTIC SYNDROME, TYPE 9	OMIM Accession: SCV000109559.2 First in ClinVar: Dec 25, 2013 Last updated: Nov 10, 2016	Publications: PubMed (1) PubMed: 24270420 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided 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 (Mar 13, 2018) N Not contributing to aggregate classification	no assertion criteria provided	Nephrotic syndrome, type 9	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare Accession: SCV000863832.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Sep 26, 2019) N Not contributing to aggregate classification	no assertion criteria provided	Nephrotic syndrome, type 9	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001133137.1 First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	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	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	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	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

not provided (-) N Not contributing to aggregate classification	no classification provided	Nephrotic syndrome, type 9	GeneReviews Accession: SCV000494108.2 First in ClinVar: Nov 10, 2016 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 24270420 BookShelf: NBK410087 BookShelf: NBK410087 Observation: 1 Collection method: literature only Allele origin: germline Affected status: unknown Observation 1 Collection method: literature only Allele origin: germline Affected status: unknown

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:

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). 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 missense change has been observed in individuals with COQ8B-related conditions (PMID: 24270420, 28204945, 28454995, 29382012, 31130284, 31937884, 32543055, 32604935, 32859164, 34605136). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91845). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COQ8B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects COQ8B function (PMID: 29194833). For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

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
Long-term nephrotic syndrome recurrence risk of kidney transplantation in two siblings with ADCK4-associated glomerulopathy.	Wang S	Pediatric transplantation	2022	PMID: 34605136
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 ...

These 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 Mar 08, 2026