6-42704546-G-A

Position:

• chr6-42704546-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000322.5(PRPH2):​c.647C>T​(p.Pro216Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,888 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P216R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRPH2 NM_000322.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 U:1 O:1
• Conservation: PhyloP100: 6.80

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 15 ACMG points.

• 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• PP5: Variant 6-42704546-G-A is Pathogenic according to our data. Variant chr6-42704546-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42704546-G-A is described in Lovd as [Pathogenic]. Variant chr6-42704546-G-A is described in Lovd as [Likely_pathogenic]. Variant chr6-42704546-G-A is described in Lovd as [Likely_pathogenic]. Variant chr6-42704546-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPH2	NM_000322.5	c.647C>T	p.Pro216Leu	missense_variant	2/3	ENST00000230381.7	NP_000313.2
PRPH2	XR_007059288.1	n.1092C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPH2	ENST00000230381.7	c.647C>T	p.Pro216Leu	missense_variant	2/3	1	NM_000322.5	ENSP00000230381	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251438 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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 Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Apr 06, 2021	Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Global Variome, with Curator vacancy, Julia Lopez, LOVD, Manon Peeters. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2015	The P216L variant in the PRPH2 gene has been reported previously in association with autosomal dominantretinitis pigmentosa (Loewen et al., 2003; Kajiwara et al., 1991). The P216L variant was not observed inapproximately 6,500 samples from individuals of European and African American ancestry in the NHLBI ESPExome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret P216L as a pathogenic variant. -

Retinal dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 03, 2019	- -
Pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -

Retinitis pigmentosa Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	Jan 07, 2020	The variant NM_000322.4:c.647C>T in the PRPH2 gene has been previously studied(PMIDs 1684223, 12925772, 28559085). We found this variant in 3 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755806,CM910324). It is present in gnomAD browser (AF 0.00000406). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-M, PM1, PM2, PM3, PM5, PP3, PP5] and classified NM_000322.4:c.647C>T in the PRPH2 gene as a Pathogenic mutation. -

Patterned dystrophy of the retinal pigment epithelium Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Jan 07, 2020

The variant NM_000322.4:c.647C>T in the PRPH2 gene has been previously studied(PMIDs 1684223, 12925772, 28559085). We found this variant in 3 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755806,CM910324). It is present in gnomAD browser (AF 0.00000406). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-M, PM1, PM2, PM3, PM5, PP3, PP5] and classified NM_000322.4:c.647C>T in the PRPH2 gene as a Pathogenic mutation. -

Retinitis pigmentosa 7 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 12, 1991

- -

PRPH2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 216 of the PRPH2 protein (p.Pro216Leu). This variant is present in population databases (rs61755806, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal dominant retinitis pigmentosa (PMID: 1684223, 28076437). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13164). 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: 12925772). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.12	D
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.65
Sift	Benign	0.051	T
Sift4G	Benign	0.15	T
Vest4		0.76
MutPred		0.67		Loss of disorder (P = 0.0239);
MVP		0.93
MPC		0.71
ClinPred		0.99	D
GERP RS		5.1
gMVP		0.90

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

Other links and lift over

dbSNP: rs61755806; hg19: chr6-42672284;