5-149944370-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_000440.3(PDE6A):c.304C>A(p.Arg102Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,614,124 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

PDE6A
NM_000440.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:19U:1

Conservation

PhyloP100: 2.03

Variant links:

Genes affected

PDE6A (HGNC:8785): (phosphodiesterase 6A) This gene encodes the cyclic-GMP (cGMP)-specific phosphodiesterase 6A alpha subunit, expressed in cells of the retinal rod outer segment. The phosphodiesterase 6 holoenzyme is a heterotrimer composed of an alpha, beta, and two gamma subunits. cGMP is an important regulator of rod cell membrane current, and its dynamic concentration is established by phosphodiesterase 6A cGMP hydrolysis and guanylate cyclase cGMP synthesis. The protein is a subunit of a key phototransduction enzyme and participates in processes of transmission and amplification of the visual signal. Mutations in this gene have been identified as one cause of autosomal recessive retinitis pigmentosa. [provided by RefSeq, Jul 2008]

PDE6A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a domain GAF 1 (size 149) in uniprot entity PDE6A_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000440.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.779

PP5

Variant 5-149944370-G-T is Pathogenic according to our data. Variant chr5-149944370-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 193099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149944370-G-T is described in Lovd as [Likely_pathogenic]. Variant chr5-149944370-G-T is described in Lovd as [Pathogenic]. Variant chr5-149944370-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE6A	NM_000440.3 link	c.304C>A	p.Arg102Ser	missense_variant	Exon 1 of 22	ENST00000255266.10	NP_000431.2	P16499
PDE6A	NM_001410788.1 link	c.304C>A	p.Arg102Ser	missense_variant	Exon 1 of 20		NP_001397717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PDE6A	ENST00000255266.10 link	c.304C>A	p.Arg102Ser	missense_variant	Exon 1 of 22	1	NM_000440.3	ENSP00000255266.5	P16499
PDE6A	ENST00000508173.5 link	n.424C>A		non_coding_transcript_exon_variant	Exon 1 of 20	1
PDE6A	ENST00000613228.1 link	c.304C>A	p.Arg102Ser	missense_variant	Exon 1 of 20	5		ENSP00000478060.1	F1T0K3

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

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:

0.000830

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251400

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135870

show subpopulations

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:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000281

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000153

AC:

223

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

130

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000168

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000105

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000831

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000176

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:19Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:6Uncertain:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 05, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 102 of the PDE6A protein (p.Arg102Ser). This variant is present in population databases (rs141252097, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive retinitis pigmentosa (arRP) (PMID: 10393062, 25775262, 26868535, 27917291). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 193099). Invitae Evidence 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 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 PDE6A protein function. For these reasons, this variant has been classified as Pathogenic. -

Clinical Genetics, Academic Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 43

Pathogenic:6

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 23, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 23, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 24, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The PDE6A c.304C>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, PP1. Based on this evidence we have classified this variant as Likely Pathogenic. -

Retinal dystrophy

Pathogenic:3

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 19, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2024

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Retinitis pigmentosa

Pathogenic:2

Sep 20, 2016

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PDE6A c.304C>A (p.Arg102Ser) missense variant has been reported in several studies. The variant was first reported by Dryja et al. (1999), who identified the variant in a compound heterozygous state in a sibling pair affected with autosomal recessive retinitis pigmentosa (arRP) and in a heterozygous state in the unaffected father and an unaffected sibling. Maria et al. (2015) later reported the variant in a homozygous state in a total of five individuals, including two sibling pairs, from a large consanguineous family affected with arRP. The variant was also identified in a heterozygous state in nine unaffected family members. The p.Arg102Ser variant has been further reported in 14 additional individuals, including in a heterozygous state with no second identified variant in a sibling pair affected with arRP, in 11 individuals with arRP where zygosity information is not provided, and in a heterozygous state in an individual with an unidentified retinal disorder (Avila-Fernandez et al. 2010; Booij et al. 2011; Abu-Safieh et al. 2013; van Huet et al. 2015). The p.Arg102Ser variant was absent from 70 controls (Dryja et al. 1999) and is reported at a frequency of 0.00018 in the South Asian population of the Exome Aggregation Consortium. The Arg102 residue is located in the GMP binding domain in exon 1 and is conserved (Dryja et al. 1999). Based on the collective evidence, the p.Arg102Ser 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. -

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

PDE6A-related disorder

Pathogenic:1

Sep 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PDE6A c.304C>A variant is predicted to result in the amino acid substitution p.Arg102Ser. This variant has been reported in the homozygous and compound heterozygous states in many individuals with retinal disease (see for examples: Dryja et al. 1999. PubMed ID: 10393062; Table S1, Holtan et al. 2019. PubMed ID: 31429209; Table S2, Sharon et al. 2019. PubMed ID: 31456290; Table S1, Lin et al. 2024. PubMed ID: 38219857). This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Given the evidence, we interpret this variant as pathogenic. -

Autosomal recessive retinitis pigmentosa

Pathogenic:1

Oct 26, 2012

Faculty of Health Sciences, Beirut Arab University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;D;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Benign

0.74

LIST_S2

Pathogenic

0.98

D;D;.

M_CAP

Benign

0.046

MetaRNN

Pathogenic

0.78

D;D;D

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.3

.;M;.

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.5

.;D;.

REVEL

Uncertain

0.57

Sift

Benign

0.13

.;T;.

Sift4G

Benign

0.12

T;T;T

Polyphen

1.0

.;D;.

Vest4

0.86

MVP

0.92

MPC

0.52

ClinPred

0.44

GERP RS

4.5

Varity_R

0.69

gMVP

0.32

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over