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rs61755781

chr6-42721913-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000322.5(PRPH2):c.422A>G(p.Tyr141Cys) variant causes a missense 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. 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. Y141D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PRPH2
NM_000322.5 missense

Scores

12
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 7.98
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000322.5
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
    PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr6-42721914-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2748549.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.982
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 6-42721913-T-C is Pathogenic according to our data. Variant chr6-42721913-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 98666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42721913-T-C is described in Lovd as [Likely_pathogenic]. Variant chr6-42721913-T-C is described in Lovd as [Pathogenic]. Variant chr6-42721913-T-C is described in Lovd as [Likely_pathogenic]. Variant chr6-42721913-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PRPH2NM_000322.5 linkuse as main transcriptc.422A>G p.Tyr141Cys missense_variant 1/3 ENST00000230381.7
PRPH2XR_007059288.1 linkuse as main transcriptn.685A>G non_coding_transcript_exon_variant 1/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PRPH2ENST00000230381.7 linkuse as main transcriptc.422A>G p.Tyr141Cys missense_variant 1/31 NM_000322.5 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461894
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727248
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
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3Other:1
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 22, 2017- -
not provided, no classification providedliterature onlyRetina International-- -
Pathogenic, no assertion criteria providedcurationLeiden Open Variation DatabaseJun 25, 2021Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Julia Lopez, LOVD, Manon Peeters. -
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 18, 2020Published functional studies demonstrate a damaging effect (alteration of PRPH2 protein complex formation) (Stuck et al., 2014); Not observed in large population cohorts (Lek et al., 2016); 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: 32531846, 28559085, 29961824, 28053051, 15370544, 12882809, 11139241, 25082885, 25097241, 22466463, 25001182) -
PRPH2-Related Disorders Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 19, 2024This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 141 of the PRPH2 protein (p.Tyr141Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa or pattern dystrophy (PMID: 16113362, 16799052, 25082885, 25097241). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 98666). 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: 25001182). For these reasons, this variant has been classified as Pathogenic. -
Vitelliform macular dystrophy 3 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2014- -
Patterned dystrophy of the retinal pigment epithelium Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingNEI Ophthalmic Genomics Laboratory, National Institutes of HealthJan 07, 2020The variant NM_000322.4:c.422A>G in the PRPH2 gene has been previously studied (PMIDs 11139241, 15370544, 22466463, 25082885, 25001182, 25097241, 28559085). We found this variant in 14 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755781,CM010125). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS3, PS4, PM1, PM2, PP3, PP5, PP1-S] and classified NM_000322.4:c.422A>G in the PRPH2 gene as a Pathogenic mutation. -
Patterned macular dystrophy 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2014- -
Cone-rod dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingNEI Ophthalmic Genomics Laboratory, National Institutes of HealthJan 07, 2020The variant NM_000322.4:c.422A>G in the PRPH2 gene has been previously studied (PMIDs 11139241, 15370544, 22466463, 25082885, 25001182, 25097241, 28559085). We found this variant in 14 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755781,CM010125). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS3, PS4, PM1, PM2, PP3, PP5, PP1-S] and classified NM_000322.4:c.422A>G in the PRPH2 gene as a Pathogenic mutation. -
Autosomal recessive bestrophinopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Molecular Genetics, University of ZurichJan 30, 2021- -
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsJul 31, 2019- -
Stargardt disease Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingNEI Ophthalmic Genomics Laboratory, National Institutes of HealthJan 07, 2020The variant NM_000322.4:c.422A>G in the PRPH2 gene has been previously studied (PMIDs 11139241,15370544, 22466463, 25082885, 25001182, 25097241, 28559085). We found this variant in 14 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755781,CM010125). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS3, PS4, PM1, PM2, PP3, PP5, PP1-S] and classified NM_000322.4:c.422A>G in the PRPH2 gene as a Pathogenic mutation. -
Retinitis pigmentosa Pathogenic:1
Pathogenic, criteria provided, single submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardApr 01, 2021The p.Tyr141Cys variant in PRPH2 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PS3, PP1, PS4. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.46
Cadd
Pathogenic
30
Dann
Uncertain
1.0
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Pathogenic
0.29
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
0.87
D
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-7.4
D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Vest4
0.97
MutPred
0.88
Loss of disorder (P = 0.0932);
MVP
0.98
MPC
1.2
ClinPred
1.0
D
GERP RS
6.2
gMVP
0.96

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.

Other links and lift over

dbSNP: rs61755781; hg19: chr6-42689651; API