NM_000283.4(PDE6B):c.299G>A (p.Arg100His) AND Retinitis pigmentosa

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 1, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000779449.13

Allele description [Variation Report for NM_000283.4(PDE6B):c.299G>A (p.Arg100His)]

NM_000283.4(PDE6B):c.299G>A (p.Arg100His)

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.299G>A (p.Arg100His)

HGVS:

NC_000004.12:g.625925G>A
NG_009839.1:g.5352G>A
NM_000283.4:c.299G>AMANE SELECT
NM_001145291.2:c.299G>A
NP_000274.2:p.Arg100His
NP_000274.3:p.Arg100His
NP_001138763.2:p.Arg100His
NC_000004.11:g.619714G>A
NM_000283.3:c.299G>A
P35913:p.Arg100His

Protein change:

R100H

Links:

UniProtKB: P35913#VAR_068361; dbSNP: rs555600300

NCBI 1000 Genomes Browser:

rs555600300

Molecular consequence:

NM_000283.4:c.299G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001145291.2:c.299G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Retinitis pigmentosa (RP)
Synonyms:: Tapetoretinal degeneration
Identifiers:: MONDO: MONDO:0019200; MeSH: D012174; MedGen: C0035334; Orphanet: 791; OMIM: 268000; OMIM: PS268000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000916070	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Sep 5, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25472526, 26667666, 22334370 Citation Link,
SCV000967635	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Feb 19, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22334370, 26667666, 24033266
SCV001950324	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 1, 2021)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 28981474, 26667666, 25472526, 22334370, 25741868, 34906470

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000916070

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Uncertain significance
(Sep 5, 2017)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000967635

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Feb 19, 2016)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001950324

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 1, 2021)

germline

curation

PubMed (6)
[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	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

The Genetic Basis of Pericentral Retinitis Pigmentosa-A Form of Mild Retinitis Pigmentosa.

Comander J, Weigel-DiFranco C, Maher M, Place E, Wan A, Harper S, Sandberg MA, Navarro-Gomez D, Pierce EA.

Genes (Basel). 2017 Oct 5;8(10). doi:pii: E256. 10.3390/genes8100256.

PubMed [citation]

PMID:: 28981474
PMCID:: PMC5664106

See all PubMed Citations (7)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000916070.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The PDE6B c.299G>A (p.Arg100His) missense variant has been reported in a presumed compound heterozygous state in three individuals with retinitis pigmentosa (Neveling et al. 2012; Ge et al. 2015; Zhao et al. 2015). Control data are not available for this variant which is reported at a frequency of 0.000170 in the European (non-Finnish) population in the Exome Aggregation Consortium. The evidence for this variant is limited. Therefore, the p.Arg100His variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967635.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

The p.Arg100His variant in PDE6B has been reported in 2 individuals with isolate d Retinitis pigmentosa. Both patients were compound heterozygous with a second p athogenic allele (Neveling 2012, Ge 2015). It has also been identified in 0.017% (5/29388) of European chromosomes by the Exome Aggregation Consortium (http://e xac.broadinstitute.org/; dbSNP rs555600300). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, although additional studies are require d to fully establish its clinical significance, this variant is likely pathogeni c.

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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001950324.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

Description

The p.Arg100His 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. 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.

#	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

Last Updated: Nov 3, 2024

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