The L527P variant in the PDE6B gene has been reported previously in association with autosomal recessive retinitis pigmentosa (McLaughlin et al., 1995; Carss et al., 2017). The L527P variant is observed in 16/111,416 (0.0144%) alleles from individuals of non-Finnish European background in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). The L527P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret L527P as a likely pathogenic variant.
ClinVar Genomic variation as it relates to human health
NM_000283.4(PDE6B):c.1580T>C (p.Leu527Pro)
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.
(9)
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.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(2); Uncertain significance(4)
Pathogenic(1); Likely pathogenic(2); Uncertain significance(4)
9
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000283.4(PDE6B):c.1580T>C (p.Leu527Pro)
Variation ID: 378339 Accession: VCV000378339.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 4p16.3 4: 660579 (GRCh38) [ NCBI UCSC ] 4: 654368 (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 Mar 8, 2017 Feb 14, 2024 Jun 24, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000283.4:c.1580T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000274.3:p.Leu527Pro missense NM_001145291.2:c.1580T>C NP_001138763.2:p.Leu527Pro missense NM_001145292.2:c.743T>C NP_001138764.2:p.Leu248Pro missense NM_001350154.3:c.743T>C NP_001337083.1:p.Leu248Pro missense NM_001350155.3:c.425T>C NP_001337084.1:p.Leu142Pro missense NM_001379246.1:c.743T>C NP_001366175.1:p.Leu248Pro missense NM_001379247.1:c.743T>C NP_001366176.1:p.Leu248Pro missense NC_000004.12:g.660579T>C NC_000004.11:g.654368T>C NG_009839.1:g.40006T>C - Protein change
- L527P, L248P, L142P
- Other names
- -
- Canonical SPDI
- NC_000004.12:660578:T:C
-
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) 0.00008
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00007
- 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. |
|||
| PDE6B | - | - |
GRCh38 GRCh37 |
976 | 1265 | |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 24, 2023 | RCV000427120.8 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 1, 2021 | RCV000504854.8 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Apr 8, 2021 | RCV000845026.6 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 28, 2017 | RCV001154208.4 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Aug 15, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000514085.4
First in ClinVar: Mar 08, 2017 Last updated: Apr 17, 2019 |
Comment:
The L527P variant in the PDE6B gene has been reported previously in association with autosomal recessive retinitis pigmentosa (McLaughlin et al., 1995; Carss et al., … (more)
The L527P variant in the PDE6B gene has been reported previously in association with autosomal recessive retinitis pigmentosa (McLaughlin et al., 1995; Carss et al., 2017). The L527P variant is observed in 16/111,416 (0.0144%) alleles from individuals of non-Finnish European background in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). The L527P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret L527P as a likely pathogenic variant. (less)
|
|
|
Uncertain significance
(Nov 14, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000916071.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The PDE6B c.1580T>C (p.Leu527Pro) missense variant has been reported in a compound heterozygous state in three individuals, including a sibling pair, with retinitis pigmentosa (McLaughlin … (more)
The PDE6B c.1580T>C (p.Leu527Pro) missense variant has been reported in a compound heterozygous state in three individuals, including a sibling pair, with retinitis pigmentosa (McLaughlin et al. 1995; Carss et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00015 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the limited evidence, the p.Leu527Pro variant is classified as a variant of unknown significance but suspicious for pathogenicity for the recessive form of retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Uncertain significance
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital stationary night blindness autosomal dominant 2
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001315544.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
|
Likely pathogenic
(Mar 07, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa 40
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369848.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS4,PM1,PM2,PP3,PP4.
|
|
|
Uncertain significance
(Apr 08, 2021)
|
criteria provided, single submitter
Method: research
|
Retinitis pigmentosa 40
Affected status: yes
Allele origin:
germline
|
Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573595.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The PDE6B c.1580T>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more)
The PDE6B c.1580T>C 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: PM2, PM3. Based on this evidence we have classified this variant as Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Apr 01, 2021)
|
criteria provided, single submitter
Method: curation
|
Retinitis pigmentosa
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001950323.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
The p.Leu527Pro variant in PDE6B was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more)
The p.Leu527Pro variant in PDE6B 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: PM2, PM3. Based on this evidence we have classified this variant as a Variant of Uncertain Significance. If you have any questions about the classification please reach out to the Pierce Lab. (less)
|
|
|
Pathogenic
(Jun 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002237664.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PDE6B protein function. ClinVar contains an entry for this variant (Variation ID: 378339). This variant is also known as T>C transition at position 18075. This missense change has been observed in individual(s) with autosomal recessive PDE6B-related conditions (PMID: 7724547, 28041643, 28559085, 30998820). 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 (rs760766981, gnomAD 0.01%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 527 of the PDE6B protein (p.Leu527Pro). (less)
|
|
|
Likely pathogenic
(Jan 01, 2015)
|
no assertion criteria provided
Method: research
|
Retinitis pigmentosa
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000599139.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Observation 1:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: European
Observation 2:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: European
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Retinitis pigmentosa 40
Affected status: yes
Allele origin:
paternal
|
GenomeConnect, ClinGen
Accession: SCV000986861.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Comment:
Variant interpretted as Likely pathogenic and reported on 08/20/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpretted as Likely pathogenic and reported on 08/20/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormality of vision (present) , Abnormal retinal morphology (present)
Age: 20-29 years
Sex: male
Testing laboratory: GeneDx
Date variant was reported to submitter: 2018-08-20
Testing laboratory interpretation: Likely pathogenic
|
Comment:
Comment:
The PDE6B c.1580T>C (p.Leu527Pro) missense variant has been reported in a compound heterozygous state in three individuals, including a sibling pair, with retinitis pigmentosa (McLaughlin et al. 1995; Carss et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00015 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the limited evidence, the p.Leu527Pro variant is classified as a variant of unknown significance but suspicious for pathogenicity for the recessive form of retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS4,PM1,PM2,PP3,PP4.
Comment:
The PDE6B c.1580T>C 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: PM2, PM3. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Comment:
The p.Leu527Pro variant in PDE6B 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: PM2, PM3. Based on this evidence we have classified this variant as a Variant of Uncertain Significance. If you have any questions about the classification please reach out to the Pierce Lab.
Comment:
For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PDE6B protein function. ClinVar contains an entry for this variant (Variation ID: 378339). This variant is also known as T>C transition at position 18075. This missense change has been observed in individual(s) with autosomal recessive PDE6B-related conditions (PMID: 7724547, 28041643, 28559085, 30998820). 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 (rs760766981, gnomAD 0.01%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 527 of the PDE6B protein (p.Leu527Pro).
Comment:
Variant interpretted as Likely pathogenic and reported on 08/20/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
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 L527P variant in the PDE6B gene has been reported previously in association with autosomal recessive retinitis pigmentosa (McLaughlin et al., 1995; Carss et al., 2017). The L527P variant is observed in 16/111,416 (0.0144%) alleles from individuals of non-Finnish European background in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). The L527P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret L527P as a likely pathogenic variant.
Comment:
The PDE6B c.1580T>C (p.Leu527Pro) missense variant has been reported in a compound heterozygous state in three individuals, including a sibling pair, with retinitis pigmentosa (McLaughlin et al. 1995; Carss et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00015 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the limited evidence, the p.Leu527Pro variant is classified as a variant of unknown significance but suspicious for pathogenicity for the recessive form of retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS4,PM1,PM2,PP3,PP4.
Comment:
The PDE6B c.1580T>C 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: PM2, PM3. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Comment:
The p.Leu527Pro variant in PDE6B 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: PM2, PM3. Based on this evidence we have classified this variant as a Variant of Uncertain Significance. If you have any questions about the classification please reach out to the Pierce Lab.
Comment:
For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PDE6B protein function. ClinVar contains an entry for this variant (Variation ID: 378339). This variant is also known as T>C transition at position 18075. This missense change has been observed in individual(s) with autosomal recessive PDE6B-related conditions (PMID: 7724547, 28041643, 28559085, 30998820). 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 (rs760766981, gnomAD 0.01%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 527 of the PDE6B protein (p.Leu527Pro).
Comment:
Variant interpretted as Likely pathogenic and reported on 08/20/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Longitudinal Clinical Follow-up and Genetic Spectrum of Patients With Rod-Cone Dystrophy Associated With Mutations in PDE6A and PDE6B. | Khateb S | JAMA ophthalmology | 2019 | PMID: 30998820 |
| Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. | Stone EM | Ophthalmology | 2017 | PMID: 28559085 |
| Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease. | Carss KJ | American journal of human genetics | 2017 | PMID: 28041643 |
| Mutation spectrum of the gene encoding the beta subunit of rod phosphodiesterase among patients with autosomal recessive retinitis pigmentosa. | McLaughlin ME | Proceedings of the National Academy of Sciences of the United States of America | 1995 | PMID: 7724547 |
Text-mined citations for rs760766981 ...
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 03, 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.