rs61755783

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000322.5(PRPH2):c.424C>T(p.Arg142Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,030 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. R142Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

PRPH2
NM_000322.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22O:1

Conservation

PhyloP100: 1.81

Variant links:

Genes affected

PRPH2 (HGNC:9942): (peripherin 2) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein found in the outer segment of both rod and cone photoreceptor cells. It may function as an adhesion molecule involved in stabilization and compaction of outer segment disks or in the maintenance of the curvature of the rim. This protein is essential for disk morphogenesis. Defects in this gene are associated with both central and peripheral retinal degenerations. Some of the various phenotypically different disorders are autosomal dominant retinitis pigmentosa, progressive macular degeneration, macular dystrophy and retinitis pigmentosa digenic. [provided by RefSeq, Jul 2008]

PRPH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a topological_domain Lumenal (size 140) in uniprot entity PRPH2_HUMAN there are 250 pathogenic changes around while only 6 benign (98%) in NM_000322.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-42721910-C-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.895

PP5

Variant 6-42721911-G-A is Pathogenic according to our data. Variant chr6-42721911-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42721911-G-A is described in Lovd as [Pathogenic]. Variant chr6-42721911-G-A is described in Lovd as [Pathogenic]. Variant chr6-42721911-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPH2	NM_000322.5 link	c.424C>T	p.Arg142Trp	missense_variant	Exon 1 of 3	ENST00000230381.7	NP_000313.2	P23942
PRPH2	XR_007059288.1 link	n.687C>T		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRPH2	ENST00000230381.7 link	c.424C>T	p.Arg142Trp	missense_variant	Exon 1 of 3	1	NM_000322.5	ENSP00000230381.5		P23942

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152136

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251422

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74326

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000404

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6Other:1

May 14, 2021

Leiden Open Variation Database

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Global Variome, with Curator vacancy, Johan den Dunnen, Kornelia Neveling, LOVD, Manon Peeters. Comment: Variant observed de novo. -

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 07, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in individuals with autosomal dominant retinitis pigmentosa (PMID: 22334370, 28076437); Considered a founder variant in individuals from the southeastern region of the Netherlands (PMID: 19243827); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29555955, 34411390, 34647987, 34828423, 23891399, 8644804, 28076437, 17653047, 11139263, 11801511, 19038374, 30910914, 31047497, 30215852, 29155698, 28559085, 30718709, 31456290, 32531846, 31589614, 33846575, 36011402, 34906036, 33546218, 38041245, 38453143, 22334370, 38540785, 39382871, 36284460, 38743414, 38219857, 38474159, 19243827, 22003107) -

Mar 17, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Patterned macular dystrophy 1

Pathogenic:4

Jan 30, 2021

Institute of Medical Molecular Genetics, University of Zurich

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 21, 2022

Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 15, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2025

SingHealth Duke-NUS Institute of Precision Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant is in a mutational hotspot where >50% of variants are pathogenic (PM1). gnomAD exomes and genomes homozygous allele count is less than 0 (PM2). Prevalence in affected individuals is significantly increased (PS4, PMID:32531846;34411390;32531846;28559085;8747448). Cosegregation is observed in multiple families (PP1, PMID: 34906036) -

Retinal dystrophy

Pathogenic:3

Mar 27, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Stargardt disease

Pathogenic:2

Jan 07, 2020

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant NM_000322.4:c.424C>T in the PRPH2 gene has been previously studied(PMIDs 7875944, 22003107, 22334370, 28559085, 28076437, 29555955, 29155698, 30215852, 30910914). We found this variant in 5 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755783,CM951116). It is present in gnomAD browser (AF 0.0000163). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.424C>T in the PRPH2 gene as a Pathogenic mutation. -

Dec 13, 2022

Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Progressive cone dystrophy (without rod involvement)

Pathogenic:1

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Patterned dystrophy of the retinal pigment epithelium

Pathogenic:1

Jan 07, 2020

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Choroidal dystrophy, central areolar 2

Pathogenic:1

Jun 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

PRPH2-related disorder

Pathogenic:1

Jan 19, 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 tryptophan, which is neutral and slightly polar, at codon 142 of the PRPH2 protein (p.Arg142Trp). This variant is present in population databases (rs61755783, gnomAD 0.006%). This missense change has been observed in individuals with autosomal dominant pattern dystrophy, mild central areolarchoroidal dystrophy, or other retinal disease (PMID: 8644804, 19038374, 19243827, 28076437, 28559085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13183). 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 PRPH2 protein function. For these reasons, this variant has been classified as Pathogenic. -

maculopathy

Pathogenic:1

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Cone dystrophy

Pathogenic:1

Sep 01, 2016

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinitis pigmentosa

Pathogenic:1

Jan 07, 2020

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.94

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.23

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.84

MutPred

0.65

Loss of disorder (P = 0.0165);

MVP

0.92

MPC

0.98

ClinPred

0.97

GERP RS

1.9

gMVP

0.85

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