The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.96). It has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000807582). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 28117207). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_182476.3(COQ6):c.782C>T (p.Pro261Leu)
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.
(5)
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
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_182476.3(COQ6):c.782C>T (p.Pro261Leu)
Variation ID: 807582 Accession: VCV000807582.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q24.3 14: 73959223 (GRCh38) [ NCBI UCSC ] 14: 74425926 (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 Feb 3, 2020 Feb 14, 2024 Jan 22, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_182476.3:c.782C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_872282.1:p.Pro261Leu missense NM_001330189.2:c.*307G>A 3 prime UTR NM_001382258.1:c.1201-3636G>A intron variant NM_001382259.1:c.*307G>A 3 prime UTR NM_001382260.1:c.*307G>A 3 prime UTR NM_001382262.1:c.1201-3395G>A intron variant NM_001425255.1:c.782C>T NP_001412184.1:p.Pro261Leu missense NM_001425256.1:c.782C>T NP_001412185.1:p.Pro261Leu missense NM_001425257.1:c.617C>T NP_001412186.1:p.Pro206Leu missense NM_001425258.1:c.707C>T NP_001412187.1:p.Pro236Leu missense NM_001425259.1:c.557C>T NP_001412188.1:p.Pro186Leu missense NM_001425260.1:c.557C>T NP_001412189.1:p.Pro186Leu missense NM_001425261.1:c.557C>T NP_001412190.1:p.Pro186Leu missense NM_001425262.1:c.527C>T NP_001412191.1:p.Pro176Leu missense NM_001425263.1:c.455C>T NP_001412192.1:p.Pro152Leu missense NM_001425264.1:c.242C>T NP_001412193.1:p.Pro81Leu missense NM_001425265.1:c.242C>T NP_001412194.1:p.Pro81Leu missense NM_182480.3:c.707C>T NP_872286.2:p.Pro236Leu missense NC_000014.9:g.73959223C>T NC_000014.8:g.74425926C>T NG_032805.1:g.14290C>T - Protein change
- P261L, P236L
- Other names
- -
- Canonical SPDI
- NC_000014.9:73959222:C:T
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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) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00006
The Genome Aggregation Database (gnomAD) 0.00011
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
- 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. |
|||
| COQ6 | - | - |
GRCh38 GRCh37 |
70 | 319 | |
| ENTPD5 | - | - |
GRCh38 GRCh37 |
23 | 256 | |
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2022 | RCV000995743.17 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 22, 2024 | RCV001575270.14 |
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
(Jun 07, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial steroid-resistant nephrotic syndrome with sensorineural deafness
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001150071.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
|
|
|
Likely pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial steroid-resistant nephrotic syndrome with sensorineural deafness
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002573297.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). While this variant results in missense change, … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.96). It has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000807582). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 28117207). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Proteinuria (present) , Microscopic hematuria (present)
|
|
|
Pathogenic
(Aug 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001802229.2
First in ClinVar: Aug 21, 2021 Last updated: Aug 31, 2023 |
Comment:
Published functional studies involving transfection of P261L into COQ6 deficient yeast failed to rescue growth and mitochondrial complex II and III activity (Gigante et al., … (more)
Published functional studies involving transfection of P261L into COQ6 deficient yeast failed to rescue growth and mitochondrial complex II and III activity (Gigante et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 31937884, 30232548, 28044327, 28117207, 30584653, 35483523, 36245711) (less)
|
|
|
Pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003442735.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 261 of the COQ6 protein (p.Pro261Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 261 of the COQ6 protein (p.Pro261Leu). This variant is present in population databases (rs371260604, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of coenzyme Q10 deficiency (PMID: 28044327, 28117207, 30584653, 31937884). 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: 807582). 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. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 04, 2021)
|
no assertion criteria provided
Method: literature only
|
COENZYME Q10 DEFICIENCY, PRIMARY, 6
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV001468322.1
First in ClinVar: Jan 09, 2021 Last updated: Jan 09, 2021 |
Comment on evidence:
For discussion of the c.782C-T transition in the COQ6 gene, resulting in a pro261-to-leu (P261L) substitution, that was found in compound heterozygous state in 5 … (more)
For discussion of the c.782C-T transition in the COQ6 gene, resulting in a pro261-to-leu (P261L) substitution, that was found in compound heterozygous state in 5 patients with coenzyme Q10 deficiency-6 (COQ10D6; 614650) by Park et al. (2017), see 614647.0008. (less)
|
Comment:
Comment:
Published functional studies involving transfection of P261L into COQ6 deficient yeast failed to rescue growth and mitochondrial complex II and III activity (Gigante et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 31937884, 30232548, 28044327, 28117207, 30584653, 35483523, 36245711)
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 261 of the COQ6 protein (p.Pro261Leu). This variant is present in population databases (rs371260604, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of coenzyme Q10 deficiency (PMID: 28044327, 28117207, 30584653, 31937884). 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: 807582). 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. For these reasons, this variant has been classified as Pathogenic.
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 variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.96). It has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000807582). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 28117207). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Published functional studies involving transfection of P261L into COQ6 deficient yeast failed to rescue growth and mitochondrial complex II and III activity (Gigante et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 31937884, 30232548, 28044327, 28117207, 30584653, 35483523, 36245711)
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 261 of the COQ6 protein (p.Pro261Leu). This variant is present in population databases (rs371260604, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of coenzyme Q10 deficiency (PMID: 28044327, 28117207, 30584653, 31937884). 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: 807582). 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. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Comprehensive genetic diagnosis of Japanese patients with severe proteinuria. | Nagano C | Scientific reports | 2020 | PMID: 31937884 |
| Pair analysis and custom array CGH can detect a small copy number variation in COQ6 gene. | Nakanishi K | Clinical and experimental nephrology | 2019 | PMID: 30584653 |
| COQ6 Mutations in Children With Steroid-Resistant Focal Segmental Glomerulosclerosis and Sensorineural Hearing Loss. | Park E | American journal of kidney diseases : the official journal of the National Kidney Foundation | 2017 | PMID: 28117207 |
| Further phenotypic heterogeneity of CoQ10 deficiency associated with steroid resistant nephrotic syndrome and novel COQ2 and COQ6 variants. | Gigante M | Clinical genetics | 2017 | PMID: 28044327 |
Text-mined citations for rs371260604 ...
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 30, 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.