rs61755806

Positions:

Variant summary

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

The NM_000322.5(PRPH2):c.647C>T(p.Pro216Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,888 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P216R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PRPH2
NM_000322.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8U:1O:1

Conservation

PhyloP100: 6.80

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 15 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 chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.838

PP5

Variant 6-42704546-G-A is Pathogenic according to our data. Variant chr6-42704546-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42704546-G-A is described in Lovd as [Pathogenic]. Variant chr6-42704546-G-A is described in Lovd as [Likely_pathogenic]. Variant chr6-42704546-G-A is described in Lovd as [Likely_pathogenic]. Variant chr6-42704546-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPH2	NM_000322.5 linkuse as main transcript	c.647C>T	p.Pro216Leu	missense_variant	2/3	ENST00000230381.7	NP_000313.2
PRPH2	XR_007059288.1 linkuse as main transcript	n.1092C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPH2	ENST00000230381.7 linkuse as main transcript	c.647C>T	p.Pro216Leu	missense_variant	2/3	1	NM_000322.5	ENSP00000230381	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251438

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135902

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

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:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Apr 06, 2021	Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Global Variome, with Curator vacancy, Julia Lopez, LOVD, Manon Peeters. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2015	The P216L variant in the PRPH2 gene has been reported previously in association with autosomal dominantretinitis pigmentosa (Loewen et al., 2003; Kajiwara et al., 1991). The P216L variant was not observed inapproximately 6,500 samples from individuals of European and African American ancestry in the NHLBI ESPExome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret P216L as a pathogenic variant. -

Retinal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 03, 2019	- -
Pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -

Retinitis pigmentosa

Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	Jan 07, 2020	The variant NM_000322.4:c.647C>T in the PRPH2 gene has been previously studied(PMIDs 1684223, 12925772, 28559085). We found this variant in 3 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755806,CM910324). It is present in gnomAD browser (AF 0.00000406). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-M, PM1, PM2, PM3, PM5, PP3, PP5] and classified NM_000322.4:c.647C>T in the PRPH2 gene as a Pathogenic mutation. -

Patterned dystrophy of the retinal pigment epithelium

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Jan 07, 2020

The variant NM_000322.4:c.647C>T in the PRPH2 gene has been previously studied(PMIDs 1684223, 12925772, 28559085). We found this variant in 3 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755806,CM910324). It is present in gnomAD browser (AF 0.00000406). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-M, PM1, PM2, PM3, PM5, PP3, PP5] and classified NM_000322.4:c.647C>T in the PRPH2 gene as a Pathogenic mutation. -

Retinitis pigmentosa 7

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 12, 1991

- -

PRPH2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 216 of the PRPH2 protein (p.Pro216Leu). This variant is present in population databases (rs61755806, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant retinitis pigmentosa (PMID: 1684223, 28076437). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13164). 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) performed at Invitae 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: 12925772). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.92

M_CAP

Uncertain

0.086

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

0.12

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.65

Sift

Benign

0.051

Sift4G

Benign

0.15

Vest4

0.76

MutPred

0.67

Loss of disorder (P = 0.0239);

MVP

0.93

MPC

0.71

ClinPred

0.99

GERP RS

5.1

gMVP

0.90

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