6-42704568-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000322.5(PRPH2):​c.625G>A​(p.Val209Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,032 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V209D) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

PRPH2
NM_000322.5 missense

Scores

5
8
2

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.85
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PS1
Transcript NM_000322.5 (PRPH2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
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 chr6-42704567-A-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.89
PP5
Variant 6-42704568-C-T is Pathogenic according to our data. Variant chr6-42704568-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1067264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42704568-C-T is described in Lovd as [Pathogenic]. Variant chr6-42704568-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRPH2NM_000322.5 linkc.625G>A p.Val209Ile missense_variant 2/3 ENST00000230381.7 NP_000313.2 P23942
PRPH2XR_007059288.1 linkn.1070G>A non_coding_transcript_exon_variant 3/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRPH2ENST00000230381.7 linkc.625G>A p.Val209Ile missense_variant 2/31 NM_000322.5 ENSP00000230381.5 P23942

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152148
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251412
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135900
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000924
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000150
AC:
22
AN:
1461884
Hom.:
0
Cov.:
32
AF XY:
0.0000151
AC XY:
11
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000187
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152148
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoDec 06, 2019DNA sequence analysis of the PRPH2 gene demonstrated a sequence change, c.625G>A, in exon 2 that results in an amino acid change, p.Val209Ile. The p.Val209Ile change affects a highly conserved amino acid residue located in a domain of the PRPH2 protein that is known to be functional. The p.Val209Ile substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change was identified in a 51 year old male with adult onset foveomacular vitelliform dystrophy (bilateral); it was absent in 100 controls (PMID: 20213611). It was also reported in a patient with early-onset high myopia (PMID: 29453956). Functional studies have shown that the p.Val209Ile change results in increased splicing and protein expression (PMID: 26796962). Different sequence changes affecting the same amino acid residue (p.Val209Phe and p.Val209Asp) have also been described in patients with macular and cone-rod dystrophy (PMID: 28041643 and PMID: 29555955). This sequence change has been described in the gnomAD database with a low population frequency of 0.0028% (dbSNP rs753657349). The p.Val209Ile amino acid change occurs in a region of the PRPH2 gene where other missense sequence changes have been described in patients with ocular disorders including retinitis pigmentosa, foveamacular dystrophy, and central areolar choroidal dystrophy (PMID: 20213611). These collective evidences indicate that this sequence change is likely pathogenic. -
Pathogenic, no assertion criteria providedcurationLeiden Open Variation DatabaseApr 06, 2021Curator: Global Variome, with Curator vacancy. Submitters to LOVD: LOVD, Manon Peeters. Comment: Variant observed de novo. -
Retinitis pigmentosa 7 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testing3billionMar 22, 2022Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PRPH2 related disorder (ClinVar ID: VCV001067264). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001067308, PMID:29555955). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.631>=0.6, 3CNET: 0.941>=0.75). A missense variant is a common mechanism associated with Retinitis pigmentosa 7 and digenic form. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000317). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
PRPH2-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 01, 2022This missense change has been observed in individual(s) with clinical features of autosomal dominant macular dystrophy (PMID: 20213611). This variant is present in population databases (rs753657349, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 209 of the PRPH2 protein (p.Val209Ile). ClinVar contains an entry for this variant (Variation ID: 1067264). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Val209 amino acid residue in PRPH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29555955). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
28
DANN
Pathogenic
1.0
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Uncertain
0.94
D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.89
D
MetaSVM
Uncertain
0.60
D
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-0.93
N
REVEL
Uncertain
0.63
Sift
Uncertain
0.0050
D
Sift4G
Uncertain
0.0080
D
Vest4
0.90
MutPred
0.72
Loss of catalytic residue at V209 (P = 0.0424);
MVP
0.96
MPC
0.91
ClinPred
0.57
D
GERP RS
5.1
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs753657349; hg19: chr6-42672306; COSMIC: COSV57836140; API