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rs61755792

chr6-42721821-G-Achr6-42721821-G-Cchr6-42721821-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_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

7
7
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17O:1

Conservation

PhyloP100: 2.53
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 16 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 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr6-42721820-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.84
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 6-42721821-G-A is Pathogenic according to our data. Variant chr6-42721821-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42721821-G-A is described in Lovd as [Pathogenic]. Variant chr6-42721821-G-A is described in Lovd as [Likely_pathogenic]. Variant chr6-42721821-G-A is described in Lovd as [Pathogenic]. Variant chr6-42721821-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PRPH2NM_000322.5 linkuse as main transcriptc.514C>T p.Arg172Trp missense_variant 1/3 ENST00000230381.7
PRPH2XR_007059288.1 linkuse as main transcriptn.777C>T 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.514C>T p.Arg172Trp missense_variant 1/31 NM_000322.5 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461894
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:17Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:6Other:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
not provided, no classification providedliterature onlyRetina International-- -
Pathogenic, no assertion criteria providedcurationLeiden Open Variation DatabaseApr 27, 2021Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Global Variome, with Curator vacancy, IMGAG, Julia Lopez, LOVD, Manon Peeters, Yoshito Koyanagi. -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 30, 2023Reported 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) -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2018- -
PRPH2-Related Disorders Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 11, 2023This 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). 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: 24463884). For these reasons, this variant has been classified as Pathogenic. -
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.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
Pathogenic, criteria provided, single submitterclinical testingNEI Ophthalmic Genomics Laboratory, National Institutes of HealthJan 07, 2020The 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. -
Retinitis pigmentosa 7 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyOct 08, 2021- -
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.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. -
Patterned macular dystrophy 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Molecular Genetics, University of ZurichJan 30, 2021- -
Choroidal dystrophy, central areolar 2 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 1998- -
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitterresearchDept Of Ophthalmology, Nagoya UniversityOct 01, 2023- -
maculopathy Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchSharon lab, Hadassah-Hebrew University Medical CenterJun 23, 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.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. -
Retinitis pigmentosa Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingNEI Ophthalmic Genomics Laboratory, National Institutes of HealthJan 07, 2020The 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.080
Cadd
Pathogenic
27
Dann
Pathogenic
1.0
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.87
D
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.84
D
MetaSVM
Uncertain
0.15
D
MutationTaster
Benign
0.96
D
PrimateAI
Uncertain
0.59
T
PROVEAN
Pathogenic
-5.3
D
REVEL
Pathogenic
0.67
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Vest4
0.54
MutPred
0.74
Loss of helix (P = 0.079);
MVP
0.96
MPC
1.0
ClinPred
1.0
D
GERP RS
4.0
gMVP
0.87

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: rs61755792; hg19: chr6-42689559; COSMIC: COSV57838468; API