6-42704609-C-T

Variant names:

• chr6-42704609-C-T
• rs121918567
• NM_000322.5:c.584G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000322.5(PRPH2):​c.584G>A​(p.Arg195Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. R195P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRPH2 NM_000322.5 missense, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.85
• Publications: 25 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain 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 chr6-42704609-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 126 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 0.10182 (below the threshold of 3.09). Trascript score misZ: 0.57529 (below the threshold of 3.09). GenCC associations: The gene is linked to inherited retinal dystrophy, fundus albipunctatus, retinitis pigmentosa 7, choroidal dystrophy, central areolar 2, adult-onset foveomacular vitelliform dystrophy, retinitis punctata albescens, hereditary macular dystrophy, central areolar choroidal dystrophy, Leber congenital amaurosis, vitelliform macular dystrophy 3, multifocal pattern dystrophy simulating fundus flavimaculatus, PRPH2-related retinopathy, cone-rod dystrophy, retinitis pigmentosa, patterned macular dystrophy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 6-42704609-C-T is Pathogenic according to our data. Variant chr6-42704609-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 623212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000322.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPH2	NM_000322.5	MANE Select	c.584G>A	p.Arg195Gln	missense splice_region	Exon 2 of 3	NP_000313.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPH2	ENST00000230381.7	TSL:1 MANE Select	c.584G>A	p.Arg195Gln	missense splice_region	Exon 2 of 3	ENSP00000230381.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Patterned dystrophy of the retinal pigment epithelium Pathogenic:1

Jan 07, 2020

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant NM_000322.4:c.584G>A in the PRPH2 gene has been previously studied(PMID 25082885). We found this variant in 1 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (CM149326). It is absent in gnomAD browser. It is not enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PM1, PM2, PM5, PP3, PP5] and classified NM_000322.4:c.584G>A in the PRPH2 gene as a Likely Pathogenic mutation.

Cone-rod dystrophy Pathogenic:1

Jul 13, 2017

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Patterned macular dystrophy 1 Pathogenic:1

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Apr 06, 2021

Leiden Open Variation Database

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Global Variome, with Curator vacancy. Submitter to LOVD: Manon Peeters.

PRPH2-related disorder Pathogenic:1

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 195 of the PRPH2 protein (p.Arg195Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant PRPH2-related conditions (PMID: 25082885, 30726412, 30926958; Invitae). ClinVar contains an entry for this variant (Variation ID: 623212). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg195 amino acid residue in PRPH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14557183, 20213611, 26796962). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Retinal dystrophy Pathogenic:1

Jan 01, 2014

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-1.1	T
PhyloP100		7.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.76
Sift	Benign	0.034	D
Sift4G	Uncertain	0.048	D
Vest4		0.85
MutPred		0.73		Loss of phosphorylation at S198 (P = 0.0503)
MVP		0.59
MPC		0.93
ClinPred		0.98	D
GERP RS		5.1
gMVP		0.89
Mutation Taster		=42/58	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918567; hg19: chr6-42672347; COSMIC: COSV57836319;