rs61755786

Positions:

• chr6-42721871-GTCT-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000322.5(PRPH2):​c.461_463del​(p.Lys154del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRPH2 NM_000322.5 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.92

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 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_000322.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000322.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 6-42721871-GTCT-G is Pathogenic according to our data. Variant chr6-42721871-GTCT-G is described in ClinVar as [Pathogenic]. Clinvar id is 13178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42721871-GTCT-G is described in Lovd as [Pathogenic]. Variant chr6-42721871-GTCT-G is described in Lovd as [Likely_pathogenic]. Variant chr6-42721871-GTCT-G is described in Lovd as [Likely_pathogenic]. Variant chr6-42721871-GTCT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPH2	NM_000322.5	c.461_463del	p.Lys154del	inframe_deletion	1/3	ENST00000230381.7
PRPH2	XR_007059288.1	n.724_726del		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPH2	ENST00000230381.7	c.461_463del	p.Lys154del	inframe_deletion	1/3	1	NM_000322.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727248

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Likely pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	May 21, 2021	Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Andreas Laner, LOVD, Manon Peeters. -

Retinitis pigmentosa 7 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1993

- -

Cone-rod dystrophy 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.461_463delAGA in the PRPH2 gene has been previously studied(PMIDs 8240110, 25412400, 27365499). We found this variant in 2 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755786). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PM2, PM4, PP1, PP5] and classified NM_000322.4:c.461_463delAGA in the PRPH2 gene as a Pathogenic mutation. -

Patterned macular dystrophy 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1993

- -

PRPH2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

This variant, c.461_463del, results in the deletion of 1 amino acid(s) of the PRPH2 protein (p.Lys154del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of inherited retinal disease (PMID: 8240110; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13178). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PRPH2 function (PMID: 27365499). This variant disrupts the p.Lys154 amino acid residue in PRPH2. Other variant(s) that disrupt this residue have been observed in individuals with PRPH2-related conditions (PMID: 26161267), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Stargardt disease 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.461_463delAGA in the PRPH2 gene has been previously studied(PMIDs 8240110, 25412400, 27365499). We found this variant in 2 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs61755786). It is absent in gnomAD browser. It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PM2, PM4, PP1, PP5] and classified NM_000322.4:c.461_463delAGA in the PRPH2 gene as a Pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

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: rs61755786; hg19: chr6-42689609;