rs760766981

chr4-660579-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PP3_Strong PP5

The NM_000283.4(PDE6B):c.1580T>C(p.Leu527Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,613,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: PDE6B NM_000283.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:4 O:1
• Conservation: PhyloP100: 7.50

Genes affected

PDE6B (HGNC:8786): (phosphodiesterase 6B) Photon absorption triggers a signaling cascade in rod photoreceptors that activates cGMP phosphodiesterase (PDE), resulting in the rapid hydrolysis of cGMP, closure of cGMP-gated cation channels, and hyperpolarization of the cell. PDE is a peripheral membrane heterotrimeric enzyme made up of alpha, beta, and gamma subunits. This gene encodes the beta subunit. Mutations in this gene result in retinitis pigmentosa and autosomal dominant congenital stationary night blindness. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000283.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 4-660579-T-C is Pathogenic according to our data. Variant chr4-660579-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 378339.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Uncertain_significance=4, Likely_pathogenic=2, Pathogenic=1}. Variant chr4-660579-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE6B	NM_000283.4	c.1580T>C	p.Leu527Pro	missense_variant	12/22	ENST00000496514.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE6B	ENST00000496514.6	c.1580T>C	p.Leu527Pro	missense_variant	12/22	1	NM_000283.4	P3
PDE6B	ENST00000255622.10	c.1580T>C	p.Leu527Pro	missense_variant	12/22	1		A1
PDE6B	ENST00000429163.6	c.743T>C	p.Leu248Pro	missense_variant	10/20	2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000678 AC: 17 AN: 250680 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000472 AC: 69 AN: 1461576 Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32 AN XY: 727088

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152130 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74304

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinitis pigmentosa Pathogenic:1 Uncertain:2

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 14, 2018	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. -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Apr 01, 2021	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. -

Retinitis pigmentosa 40 Pathogenic:1 Uncertain:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 07, 2020	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS4,PM1,PM2,PP3,PP4. -
Uncertain significance, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 24, 2023	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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2018	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. -

Congenital stationary night blindness autosomal dominant 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0090	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.98
MVP		0.94
MPC		0.74
ClinPred		0.89	D
GERP RS		4.3
Varity_R		0.86
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs760766981; hg19: chr4-654368;