NM_000283.4(PDE6B):c.1580T>C (p.Leu527Pro) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 24, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000427120.8

Allele description [Variation Report for NM_000283.4(PDE6B):c.1580T>C (p.Leu527Pro)]

NM_000283.4(PDE6B):c.1580T>C (p.Leu527Pro)

Gene:

PDE6B:phosphodiesterase 6B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4p16.3

Genomic location:

Preferred name:

NM_000283.4(PDE6B):c.1580T>C (p.Leu527Pro)

HGVS:

NC_000004.12:g.660579T>C
NG_009839.1:g.40006T>C
NM_000283.4:c.1580T>CMANE SELECT
NM_001145291.2:c.1580T>C
NM_001145292.2:c.743T>C
NM_001350154.3:c.743T>C
NM_001350155.3:c.425T>C
NM_001379246.1:c.743T>C
NM_001379247.1:c.743T>C
NP_000274.2:p.Leu527Pro
NP_000274.3:p.Leu527Pro
NP_001138763.2:p.Leu527Pro
NP_001138764.2:p.Leu248Pro
NP_001337083.1:p.Leu248Pro
NP_001337084.1:p.Leu142Pro
NP_001366175.1:p.Leu248Pro
NP_001366176.1:p.Leu248Pro
NC_000004.11:g.654368T>C
NM_000283.3:c.1580T>C

Protein change:

L142P

Links:

dbSNP: rs760766981

NCBI 1000 Genomes Browser:

rs760766981

Molecular consequence:

NM_000283.4:c.1580T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001145291.2:c.1580T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001145292.2:c.743T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001350154.3:c.743T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001350155.3:c.425T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001379246.1:c.743T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001379247.1:c.743T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000514085	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Aug 15, 2018)	germline	clinical testing	Citation Link,
SCV002237664	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 24, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7724547, 28041643, 28559085, 30998820, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000514085

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(Aug 15, 2018)

germline

clinical testing

Citation Link,

SCV002237664

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 24, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation spectrum of the gene encoding the beta subunit of rod phosphodiesterase among patients with autosomal recessive retinitis pigmentosa.

McLaughlin ME, Ehrhart TL, Berson EL, Dryja TP.

Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3249-53.

PubMed [citation]

PMID:: 7724547
PMCID:: PMC42143

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.

Carss KJ, Arno G, Erwood M, Stephens J, Sanchis-Juan A, Hull S, Megy K, Grozeva D, Dewhurst E, Malka S, Plagnol V, Penkett C, Stirrups K, Rizzo R, Wright G, Josifova D, Bitner-Glindzicz M, Scott RH, Clement E, Allen L, Armstrong R, Brady AF, et al.

Am J Hum Genet. 2017 Jan 5;100(1):75-90. doi: 10.1016/j.ajhg.2016.12.003. Epub 2016 Dec 29.

PubMed [citation]

PMID:: 28041643
PMCID:: PMC5223092

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000514085.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002237664.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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