ClinVar Genomic variation as it relates to human health
NM_000440.3(PDE6A):c.1705C>A (p.Gln569Lys)
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.
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(5); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000440.3(PDE6A):c.1705C>A (p.Gln569Lys)
Variation ID: 167431 Accession: VCV000167431.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q32 5: 149895206 (GRCh38) [ NCBI UCSC ] 5: 149274769 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 29, 2015 May 12, 2024 Dec 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000440.3:c.1705C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000431.2:p.Gln569Lys missense NC_000005.10:g.149895206G>T NC_000005.9:g.149274769G>T NG_009102.1:g.54588C>A P16499:p.Gln569Lys - Protein change
- Q569K
- Other names
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- Canonical SPDI
- NC_000005.10:149895205:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00015
Exome Aggregation Consortium (ExAC) 0.00010
The Genome Aggregation Database (gnomAD), exomes 0.00012
Trans-Omics for Precision Medicine (TOPMed) 0.00012
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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PDE6A | - | - |
GRCh38 GRCh37 |
871 | 887 |
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. |
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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Dec 11, 2023 | RCV000153658.33 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2021 | RCV000292173.16 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 4, 2022 | RCV001376415.10 | |
PDE6A-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Oct 9, 2023 | RCV003416002.4 |
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. |
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Likely pathogenic
(Sep 02, 2016)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000454682.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The PDE6A c.1705C>A (p.Gln569Lys) missense variant has been reported in two studies and is found in a total of five individuals with autosomal recessive retinitis … (more)
The PDE6A c.1705C>A (p.Gln569Lys) missense variant has been reported in two studies and is found in a total of five individuals with autosomal recessive retinitis pigmentosa, including one homozygote and four compound heterozygotes (Dryja et al. 1999; Avila-Fernandez 2010). The variant is also found in a heterozygous state in six unaffected relatives of the affected individuals. The p.Gln569Lys variant was absent from 70 controls but is reported at a frequency of 0.00026 in the Latino population of the Exome Aggregation Consortium. Based on the evidence, the p.Gln569Lys variant is classified as likely pathogenic for autosomal recessive retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(Apr 08, 2021)
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criteria provided, single submitter
Method: research
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Retinitis pigmentosa 43
Affected status: yes
Allele origin:
germline
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Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573544.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The PDE6A c.1705C>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more)
The PDE6A c.1705C>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS1, PM2, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. (less)
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Pathogenic
(Mar 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001829581.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33576794, 30998820, … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33576794, 30998820, 33057649, 31736247, 26806561, 29343940, 31049658, 10393062, 30337596, 21151602) (less)
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Likely pathogenic
(Apr 01, 2021)
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criteria provided, single submitter
Method: curation
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Retinitis pigmentosa
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001950309.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
The p.Gln569Lys variant in PDE6A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more)
The p.Gln569Lys variant in PDE6A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS1, PM2. PP3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 43
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002518772.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Dec 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000948416.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 569 of the PDE6A protein (p.Gln569Lys). … (more)
This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 569 of the PDE6A protein (p.Gln569Lys). This variant is present in population databases (rs139444207, gnomAD 0.03%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 10393062, 21151602, 29343940). 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. ClinVar contains an entry for this variant (Variation ID: 167431). 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 PDE6A protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002545359.11
First in ClinVar: Jul 09, 2022 Last updated: May 12, 2024 |
Number of individuals with the variant: 2
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Uncertain significance
(Apr 07, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000203215.7
First in ClinVar: Feb 02, 2015 Last updated: Jun 29, 2015 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Oct 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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PDE6A-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004115983.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The PDE6A c.1705C>A variant is predicted to result in the amino acid substitution p.Gln569Lys. This variant has been reported many times in the compound heterozygous … (more)
The PDE6A c.1705C>A variant is predicted to result in the amino acid substitution p.Gln569Lys. This variant has been reported many times in the compound heterozygous state in individuals with retinitis pigmentosa (see for examples Bryant et al. 2017. PubMed ID: 29343940; Ezquerra-Inchausti et al. 2018. PubMed ID: 30337596; Table S2 in Zampaglione et al. 2020. PubMed ID: 32037395). This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-149274769-G-T). Given the evidence, we interpret c.1705C>A (p.Gln569Lys) as pathogenic. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK). | Zampaglione E | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906470 |
A new approach based on targeted pooled DNA sequencing identifies novel mutations in patients with Inherited Retinal Dystrophies. | Ezquerra-Inchausti M | Scientific reports | 2018 | PMID: 30337596 |
Prescreening whole exome sequencing results from patients with retinal degeneration for variants in genes associated with retinal degeneration. | Bryant L | Clinical ophthalmology (Auckland, N.Z.) | 2017 | PMID: 29343940 |
Mutation analysis of 272 Spanish families affected by autosomal recessive retinitis pigmentosa using a genotyping microarray. | Ávila-Fernández A | Molecular vision | 2010 | PMID: 21151602 |
Frequency of mutations in the gene encoding the alpha subunit of rod cGMP-phosphodiesterase in autosomal recessive retinitis pigmentosa. | Dryja TP | Investigative ophthalmology & visual science | 1999 | PMID: 10393062 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PDE6A | - | - | - | - |
Text-mined citations for rs139444207 ...
HelpRecord last updated May 27, 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.