6-42721781-A-G

Position:

chr6-42721781-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000322.5(PRPH2):c.554T>C(p.Leu185Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L185L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

PRPH2
NM_000322.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 9.21

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]

PRPH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000322.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

PP5

Variant 6-42721781-A-G is Pathogenic according to our data. Variant chr6-42721781-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42721781-A-G is described in Lovd as [Pathogenic]. Variant chr6-42721781-A-G is described in Lovd as [Likely_pathogenic]. Variant chr6-42721781-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPH2	NM_000322.5 linkuse as main transcript	c.554T>C	p.Leu185Pro	missense_variant	1/3	ENST00000230381.7
PRPH2	XR_007059288.1 linkuse as main transcript	n.817T>C		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPH2	ENST00000230381.7 linkuse as main transcript	c.554T>C	p.Leu185Pro	missense_variant	1/3	1	NM_000322.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251406

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135888

show subpopulations

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727240

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:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Patterned macular dystrophy 1

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2013	- -
Likely pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The PRPH2 c.554T>C variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PM2, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. -

not provided

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2017	The L185P variant was reported in 3 families where it functioned as a recessive variant only resultingin a disease phenotype when inherited with a null (loss-of-function) variant in the ROM1 gene ( Kajiwaraet al. 1994). Therefore the L185P variant in the PRPH2 gene and a null variant in the ROM1 genecause a digenic form of retinitis pigmentosa. The L185P substitution has also been reported previously as anapparently homozygous variant in association with Leber congenital amaurosis (Wang et al., 2013). TheL185P variant was not observed in approximately 6,500 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations. The L185P variant is a semi-conservative amino acid substitution that occurs at a positionthat is conserved across species. In silico analysis predicts this substitution is probably damaging to theprotein structure/function. Therefore, L185P is interpreted to be a pathogenic variant. -
not provided, no classification provided	literature only	Retina International	-	- -

Patterned dystrophy of the retinal pigment epithelium

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Jan 07, 2020

The variant NM_000322.4:c.554T>C in the PRPH2 gene has been previously studied(PMIDs 1684223, 8202715, 10800708, 12925772). 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 (rs121918563,CM910323). It is present in gnomAD browser (AF 0.00000812). It is not enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PP1-M, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.554T>C in the PRPH2 gene as a Likely Pathogenic mutation. -

Retinitis pigmentosa 7, digenic

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2013

- -

Leber congenital amaurosis 18

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2013

- -

PRPH2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 15, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PRPH2 function (PMID: 8943002, 11297544, 11427722, 12925772). 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. ClinVar contains an entry for this variant (Variation ID: 13165). This missense change has been observed in individuals with autosomal recessive and autosomal dominant retinal dystrophy. This variant may be associated with a milder, later-onset form of autosomal dominant retinal dystrophy (PMID: 1684223, 8202715, 9331261, 16799052, 23847139, 26720483, 32531846; Invitae). This variant is present in population databases (rs121918563, gnomAD 0.002%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 185 of the PRPH2 protein (p.Leu185Pro). -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 19, 2018

- -

Retinitis pigmentosa

Pathogenic:1

Likely pathogenic, no assertion criteria provided

curation

Leiden Open Variation Database

Apr 06, 2021

Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Feng Wang, Julia Lopez, Manon Peeters. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.51

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.3

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Vest4

0.97

MutPred

0.76

Loss of stability (P = 0.0111);

MVP

0.97

MPC

1.3

ClinPred

1.0

GERP RS

5.6

gMVP

0.97

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over