6-42704564-G-A

Position:

• chr6-42704564-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000322.5(PRPH2):​c.629C>T​(p.Pro210Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P210R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PRPH2 NM_000322.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.93

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr6-42704564-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 6-42704564-G-A is Pathogenic according to our data. Variant chr6-42704564-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 98687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42704564-G-A is described in Lovd as [Pathogenic]. Variant chr6-42704564-G-A is described in Lovd as [Likely_pathogenic]. Variant chr6-42704564-G-A is described in Lovd as [Likely_pathogenic]. Variant chr6-42704564-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPH2	NM_000322.5	c.629C>T	p.Pro210Leu	missense_variant	2/3	ENST00000230381.7
PRPH2	XR_007059288.1	n.1074C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPH2	ENST00000230381.7	c.629C>T	p.Pro210Leu	missense_variant	2/3	1	NM_000322.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

Likely pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Apr 06, 2021	Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Julia Lopez, Manon Peeters, Yoshito Koyanagi. -
not provided, no classification provided	literature only	Retina International	-	- -

PRPH2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 04, 2022

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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro210 amino acid residue in PRPH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7862413, 11139241, 17504850). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PRPH2 function (PMID: 26796962). ClinVar contains an entry for this variant (Variation ID: 98687). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 11139241, 11485765, 16799052; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 210 of the PRPH2 protein (p.Pro210Leu). -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	32
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.88	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-9.3	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.99
MutPred		0.78		Gain of stability (P = 0.0311);
MVP		0.99
MPC		0.96
ClinPred		1.0	D
GERP RS		5.1
gMVP		0.97

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

Other links and lift over

dbSNP: rs61755798; hg19: chr6-42672302;