NM_000322.5(PRPH2):c.80C>T (p.Ser27Phe) AND PRPH2-related disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 19, 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:: RCV001043298.7

Allele description [Variation Report for NM_000322.5(PRPH2):c.80C>T (p.Ser27Phe)]

NM_000322.5(PRPH2):c.80C>T (p.Ser27Phe)

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.80C>T (p.Ser27Phe)

HGVS:

NC_000006.12:g.42722255G>A
NG_009176.2:g.5366C>T
NM_000322.5:c.80C>TMANE SELECT
NP_000313.2:p.Ser27Phe
NC_000006.11:g.42689993G>A
NG_009176.1:g.5366C>T
NM_000322.4:c.80C>T

Protein change:

S27F

Links:

dbSNP: rs61755766

NCBI 1000 Genomes Browser:

rs61755766

Molecular consequence:

NM_000322.5:c.80C>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
SCV001207026	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 19, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9052636, 28492532
SCV005355297	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Likely pathogenic (Sep 13, 2024)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001207026

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 19, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005355297

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Likely pathogenic
(Sep 13, 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

Serine-27-phenylalanine mutation within the peripherin/RDS gene in a family with cone dystrophy.

Fishman GA, Stone EM, Alexander KR, Gilbert LD, Derlacki DJ, Butler NS.

Ophthalmology. 1997 Feb;104(2):299-306.

PubMed [citation]

PMID:: 9052636

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001207026.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 98711). This missense change has been observed in individuals with clinical features of autosomal dominant cone dystrophy (PMID: 9052636; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs61755766, gnomAD 0.007%). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 27 of the PRPH2 protein (p.Ser27Phe).

#	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, SCV005355297.1

#	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.80C>T variant is predicted to result in the amino acid substitution p.Ser27Phe. This variant has been reported as segregating with disease in the heterozygous state in a kindred with cone dystrophy (Fishman et al. 1997. PubMed ID: 9052636) and in the heterozygous state in several other, unrelated individuals with retinal disease (Table S1, Lin et al. 2024. PubMed ID: 38219857). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic for autosomal dominant disease.

#	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 8, 2024

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