rs121909835

Positions:

chr5-149883511-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000440.3(PDE6A):c.2053G>A(p.Val685Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,613,044 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

PDE6A
NM_000440.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.54

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:

PDE6A (HGNC:):

PDE6A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.875

PP5

Variant 5-149883511-C-T is Pathogenic according to our data. Variant chr5-149883511-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 29874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149883511-C-T is described in Lovd as [Pathogenic]. Variant chr5-149883511-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE6A	NM_000440.3 linkuse as main transcript	c.2053G>A	p.Val685Met	missense_variant	17/22	ENST00000255266.10	NP_000431.2	P16499

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PDE6A	ENST00000255266.10 linkuse as main transcript	c.2053G>A	p.Val685Met	missense_variant	17/22	1	NM_000440.3	ENSP00000255266.5	P16499
PDE6A	ENST00000508173.5 linkuse as main transcript	n.2237G>A		non_coding_transcript_exon_variant	15/20	1
PDE6A	ENST00000613228.1 linkuse as main transcript	c.1810G>A	p.Val604Met	missense_variant	15/20	5		ENSP00000478060.1	F1T0K3

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152154

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

251012

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135688

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000623

AC:

AN:

1460890

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

726868

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000702

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74334

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000103

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2023	Published functional studies in mice demonstrate a damaging effect with increased accumulation of cGMP, increased PARP activity, and severe retinal degeneration (Sothilingam et al., 2015; Jiao et al., 2016); This variant is associated with the following publications: (PMID: 18849587, 32531858, 26188004, 27551530, 21039428, 28157543, 33851411, 31589614, 33576794, 32037395, 35533076, 32553897, 33945959, 37601102, 34795310, 31884596, 34557646, 36819107, 33057649) -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 20, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 685 of the PDE6A protein (p.Val685Met). This variant is present in population databases (rs121909835, gnomAD 0.009%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 21039428, 28157543). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29874). 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 PDE6A protein function. Experimental studies have shown that this missense change affects PDE6A function (PMID: 18849587, 26188004, 27551530). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 43

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jan 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;D;D

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;.

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Uncertain

2.6

.;M;.

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.2

.;N;.

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

.;D;.

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.96

MVP

0.93

MPC

0.46

ClinPred

0.40

GERP RS

5.1

Varity_R

0.56

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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