NM_000322.5(PRPH2):c.658C>T (p.Arg220Trp) AND PRPH2-related disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 10, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001247286.8

Allele description [Variation Report for NM_000322.5(PRPH2):c.658C>T (p.Arg220Trp)]

NM_000322.5(PRPH2):c.658C>T (p.Arg220Trp)

Gene:

PRPH2:peripherin 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p21.1

Genomic location:

Preferred name:

NM_000322.5(PRPH2):c.658C>T (p.Arg220Trp)

HGVS:

NC_000006.12:g.42704535G>A
NG_009176.2:g.23086C>T
NM_000322.5:c.658C>TMANE SELECT
NP_000313.2:p.Arg220Trp
NC_000006.11:g.42672273G>A
NG_009176.1:g.23086C>T
NM_000322.4:c.658C>T

Protein change:

R220W

Links:

dbSNP: rs61755809

NCBI 1000 Genomes Browser:

rs61755809

Molecular consequence:

NM_000322.5:c.658C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: PRPH2-related disorder
Synonyms:: PRPH2-Related Disorders; PRPH2-related condition
Identifiers:: MedGen: CN239395

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001420698	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 10, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9443872, 16916875, 17653047, 29555955, 28492532
SCV005357257	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Likely pathogenic (Aug 16, 2024)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001420698

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 10, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV005357257

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Likely pathogenic
(Aug 16, 2024)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Founder effect, seen in the British population, of the 172 peripherin/RDS mutation-and further refinement of genetic positioning of the peripherin/RDS gene.

Payne AM, Downes SM, Bessant DA, Bird AC, Bhattacharya SS.

Am J Hum Genet. 1998 Jan;62(1):192-5. No abstract available.

PubMed [citation]

PMID:: 9443872
PMCID:: PMC1376804

Intrafamilial phenotypic variability in families with RDS mutations: exclusion of ROM1 as a genetic modifier for those with retinitis pigmentosa.

Leroy BP, Kailasanathan A, De Laey JJ, Black GC, Manson FD.

Br J Ophthalmol. 2007 Jan;91(1):89-93. Epub 2006 Aug 17.

PubMed [citation]

PMID:: 16916875
PMCID:: PMC1857593

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001420698.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 220 of the PRPH2 protein (p.Arg220Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant retinal dystrophy (PMID: 9443872, 16916875, 17653047, 29555955). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 98698). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRPH2 protein function. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From PreventionGenetics, part of Exact Sciences, SCV005357257.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The PRPH2 c.658C>T variant is predicted to result in the amino acid substitution p.Arg220Trp. This variant has been reported in the heterozygous state in individuals with autosomal dominant macular dystrophy (Gamundi et al. 2007. PubMed ID: 17653047; Birtel et al 2018. PubMed ID: 29555955; García Bohórquez et al. 2021. PubMed ID: 34327195 ). This variant has also been reported in an individual with early onset high myopia (Zhou et al. 2018. PubMed ID: 29453956). This variant has not been reported in the large population database gnomAD, indicating it is rare. This variant is interpreted as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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