rs61755792

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_000322.5(PRPH2):c.514C>T(p.Arg172Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,894 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. R172G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PRPH2
NM_000322.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20O:1

Conservation

PhyloP100: 2.53

Publications

72 publications found

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 Gene-Disease associations (from GenCC):

hereditary macular dystrophy
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
PRPH2-related retinopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
Leber congenital amaurosis
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
retinitis pigmentosa 7
Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
inherited retinal dystrophy
Inheritance: SD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, Ambry Genetics
choroidal dystrophy, central areolar 2
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
fundus albipunctatus
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
vitelliform macular dystrophy 3
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
adult-onset foveomacular vitelliform dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
central areolar choroidal dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
multifocal pattern dystrophy simulating fundus flavimaculatus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
patterned macular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis punctata albescens
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PRPH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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 chr6-42721821-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 98675.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 126 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 0.10182 (below the threshold of 3.09). Trascript score misZ: 0.57529 (below the threshold of 3.09). GenCC associations: The gene is linked to inherited retinal dystrophy, fundus albipunctatus, retinitis pigmentosa 7, choroidal dystrophy, central areolar 2, adult-onset foveomacular vitelliform dystrophy, retinitis punctata albescens, hereditary macular dystrophy, central areolar choroidal dystrophy, Leber congenital amaurosis, vitelliform macular dystrophy 3, multifocal pattern dystrophy simulating fundus flavimaculatus, PRPH2-related retinopathy, cone-rod dystrophy, retinitis pigmentosa, patterned macular dystrophy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.84

PP5

Variant 6-42721821-G-A is Pathogenic according to our data. Variant chr6-42721821-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPH2	NM_000322.5 link	c.514C>T	p.Arg172Trp	missense_variant	Exon 1 of 3	ENST00000230381.7	NP_000313.2
PRPH2	XR_007059288.1 link	n.777C>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.514C>T	p.Arg172Trp	missense_variant	Exon 1 of 3	1	NM_000322.5	ENSP00000230381.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6Other:1

Apr 27, 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, IMGAG, Julia Lopez, LOVD, Manon Peeters, Yoshito Koyanagi. -

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

May 30, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as a common pathogenic variant among individuals of British background (Payne et al., 1998); Published functional studies in mice demonstrate a damaging effect with defective cone photoreceptors and abnormal PRPH2(RDS)/ROM-1 complex formation (Ding et al., 2004; Conley et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21405999, 8747448, 20335603, 32531858, 18055786, 34828423, 10800708, 24463884, 9010868, 8943002, 24608669, 8302543, 8015786, 29343940, 8485576, 7493155, 22183351, 29555955, 19279306, 28838317, 31456290, 32531846, 32036094, 9810570, 33691693, 26667666, 15254014, 9443872, 34411390, 10532447) -

Clinical Genetics, Academic Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

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

- -

Patterned macular dystrophy 1

Pathogenic:2

Jan 30, 2021

Institute of Medical Molecular Genetics, University of Zurich

Significance:Likely 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 located in a mutational hotspot where >50% of variants are pathogenic (PM1). Experimental studies have shown that this missense change affects PRPH2 function (PMID:24463884;15254014). Cosegregation with disease has been found in multiple families in multiple studies (PMID:8747448;20335603;9443872) -

Choroidal dystrophy, central areolar 2

Pathogenic:2

Jan 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 02, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24463884). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.67 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.95 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013170 /PMID: 8485576 /3billion dataset). Different missense changes at the same codon (p.Arg172Gln, p.Arg172Gly, p.Arg172Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013167, VCV000098675, VCV000987409 /PMID: 8485576). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Retinal dystrophy

Pathogenic:2

Jan 01, 2018

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

- -

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

The variant NM_000322.4:c.514C>T in the PRPH2 gene has been previously studied(Nichols (1993) Invest Ophthalmol Vis Sci 34 1149). We found this variant in 13 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755792,CM930639). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.514C>T in the PRPH2 gene as a Pathogenic mutation. -

Vitelliform macular dystrophy 2

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

Retinitis pigmentosa 7

Pathogenic:1

Oct 08, 2021

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cone-rod dystrophy

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

PRPH2-related disorder

Pathogenic:1

Jan 18, 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 172 of the PRPH2 protein (p.Arg172Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant macular dystrophy (PMID: 8485576, 8747448). It has also been observed to segregate with disease in related individuals. This variant is also known as RDS p.Arg172Trp. ClinVar contains an entry for this variant (Variation ID: 13170). 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) indicates that this missense variant is expected to disrupt PRPH2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PRPH2 function (PMID: 24463884). For these reasons, this variant has been classified as Pathogenic. -

maculopathy

Pathogenic:1

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Stargardt disease

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

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

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.87

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

0.15

PhyloP100

2.5

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.3

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Vest4

0.54

MutPred

0.74

Loss of helix (P = 0.079);

MVP

0.96

MPC

1.0

ClinPred

1.0

GERP RS

4.0

gMVP

0.87

Mutation Taster

=20/80

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over