rs61755786

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_000322.5(PRPH2):c.461_463delAGA(p.Lys154del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PRPH2
NM_000322.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 7.92

Publications

5 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 13 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000322.5

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000322.5. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 6-42721871-GTCT-G is Pathogenic according to our data. Variant chr6-42721871-GTCT-G is described in ClinVar as [Pathogenic]. Clinvar id is 13178.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.461_463delAGA	p.Lys154del	disruptive_inframe_deletion	Exon 1 of 3	ENST00000230381.7	NP_000313.2	P23942
PRPH2	XR_007059288.1 link	n.724_726delAGA		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.461_463delAGA	p.Lys154del	disruptive_inframe_deletion	Exon 1 of 3	1	NM_000322.5	ENSP00000230381.5		P23942

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461894

Hom.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Other:1

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

May 21, 2021

Leiden Open Variation Database

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Andreas Laner, LOVD, Manon Peeters. -

Retinitis pigmentosa 7

Pathogenic:1

Nov 01, 1993

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

The variant NM_000322.4:c.461_463delAGA in the PRPH2 gene has been previously studied(PMIDs 8240110, 25412400, 27365499). We found this variant in 2 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755786). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PM2, PM4, PP1, PP5] and classified NM_000322.4:c.461_463delAGA in the PRPH2 gene as a Pathogenic mutation. -

Patterned macular dystrophy 1

Pathogenic:1

Nov 01, 1993

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

PRPH2-related disorder

Pathogenic:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.461_463del, results in the deletion of 1 amino acid(s) of the PRPH2 protein (p.Lys154del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of inherited retinal disease (PMID: 8240110; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13178). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PRPH2 function (PMID: 27365499). This variant disrupts the p.Lys154 amino acid residue in PRPH2. Other variant(s) that disrupt this residue have been observed in individuals with PRPH2-related conditions (PMID: 26161267), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy

Pathogenic:1

Jan 01, 2020

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.9

Mutation Taster

=45/55

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over