VCV000013167.46 - ClinVar

NM_000322.5(PRPH2):c.515G>A (p.Arg172Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(14)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000322.5(PRPH2):c.515G>A (p.Arg172Gln)

Variation ID: 13167 Accession: VCV000013167.46

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p21.1 6: 42721820 (GRCh38) [ NCBI UCSC ] 6: 42689558 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 20, 2014	Oct 20, 2024	Dec 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000322.5:c.515G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000313.2:p.Arg172Gln	missense
NC_000006.12:g.42721820C>T
NC_000006.11:g.42689558C>T
NG_009176.2:g.5801G>A

Protein change

R172Q

Other names

Canonical SPDI

NC_000006.12:42721819:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA122930 OMIM: 179605.0006 dbSNP: rs61755793 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PRPH2		-	-	GRCh38 GRCh37	752	764

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Choroidal dystrophy, central areolar 2	Pathogenic (1)	no assertion criteria provided	Mar 1, 1993	RCV000014053.23
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Oct 23, 2020	RCV000084982.30
Macular dystrophy	Pathogenic (1)	no assertion criteria provided	Apr 1, 2018	RCV000787664.2
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Aug 6, 2019	RCV001074392.4
Retinitis pigmentosa	Pathogenic (1)	no assertion criteria provided	Apr 1, 2018	RCV000787663.2
Patterned dystrophy of the retinal pigment epithelium	Pathogenic (1)	criteria provided, single submitter	Jan 7, 2020	RCV001250353.3
Stargardt disease	Pathogenic (1)	criteria provided, single submitter	Jan 7, 2020	RCV001250367.3
PRPH2-related disorder	Pathogenic (1)	criteria provided, single submitter	Dec 13, 2023	RCV001054658.8
Vitelliform macular dystrophy 3	Pathogenic (1)	criteria provided, single submitter	Dec 14, 2021	RCV001799605.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 06, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001239970.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Jan 07, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Patterned dystrophy of the retinal pigment epithelium Affected status: yes Allele origin: germline	NEI Ophthalmic Genomics Laboratory, National Institutes of Health Accession: SCV001424674.1 First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020	Comment: The variant NM_000322.4:c.515G>A in the PRPH2 gene has been previously studied(PMIDs 8485576, 22003107, 25082885, 27977834, 28559085, 29555955). We found this variant in 2 patient(s) in … (more) The variant NM_000322.4:c.515G>A in the PRPH2 gene has been previously studied(PMIDs 8485576, 22003107, 25082885, 27977834, 28559085, 29555955). 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 (rs61755793,CM930637). It is present in gnomAD browser (AF 0.00000406). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.515G>A in the PRPH2 gene as a Pathogenic mutation. (less)
Pathogenic (Jan 07, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Stargardt disease Affected status: yes Allele origin: germline	NEI Ophthalmic Genomics Laboratory, National Institutes of Health Accession: SCV001424700.1 First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020	Comment: The variant NM_000322.4:c.515G>A in the PRPH2 gene has been previously studied(PMIDs 8485576, 22003107, 25082885, 27977834, 28559085, 29555955). We found this variant in 2 patient(s) in … (more) The variant NM_000322.4:c.515G>A in the PRPH2 gene has been previously studied(PMIDs 8485576, 22003107, 25082885, 27977834, 28559085, 29555955). 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 (rs61755793,CM930637). It is present in gnomAD browser (AF 0.00000406). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.515G>A in the PRPH2 gene as a Pathogenic mutation. (less)
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447858.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Macular degeneration (present) Sex: female
Pathogenic (Dec 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Vitelliform macular dystrophy 3 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002044448.1 First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022	Comment: _x000D_ Criteria applied: PM5_STR, PP1_STR, PS4_MOD, PM2_SUP, PP3
Pathogenic (Dec 13, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	PRPH2-related disorder Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001219004.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 8485576‚ 19038374‚ 19243827 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 172 of the PRPH2 protein (p.Arg172Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 172 of the PRPH2 protein (p.Arg172Gln). This variant is present in population databases (rs61755793, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant macular dystrophy or central areolar choroidal dystrophy in families, albeit with incomplete penetrance (PMID: 8485576, 19038374, 19243827). It has also been observed to segregate with disease in related individuals. This variant is also known as RDS p.Arg172Gln. ClinVar contains an entry for this variant (Variation ID: 13167). 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. (less)
Pathogenic (Nov 01, 2017)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001249905.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Mar 01, 1993)	no assertion criteria provided Method: literature only	CHOROIDAL DYSTROPHY, CENTRAL AREOLAR, 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000034300.5 First in ClinVar: Apr 04, 2013 Last updated: Jul 03, 2020	Publications: PubMed (1) PubMed: 8485576 Boon, C. J. F., Klevering, B. J., (more...) Boon, C. J. F., Klevering, B. J., Cremers, F. P. M., Zonneveld-Vrieling, M. N., Theelen, T., Den Hollander, A. I., Hoyng, C. B. Central areolar choroidal dystrophy. Ophthalmology 116: 771-782, 2009. Comment on evidence: In 4 affected members of a family segregating autosomal dominant macular dystrophy affecting the central retina (CACD2; 613105), Wells et al. (1993) identified a G-to-A … (more) In 4 affected members of a family segregating autosomal dominant macular dystrophy affecting the central retina (CACD2; 613105), Wells et al. (1993) identified a G-to-A transition in the PRPH2 gene resulting in an arg172-to-gln (R172Q). The patients described difficulty passing from light to dark during their third or fourth decades, and visual acuity progressively worsened between the ages of 36 and 56 years. They denied night blindness or peripheral field loss. Ophthalmoscopic changes, identified by 35 years of age, consisted of macular atrophy; the peripheral fundus was normal. Boon et al. (2009) identified the R172Q mutation in 5 affected members of a Dutch family with CACD. (less)
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001954752.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Apr 01, 2018)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926652.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Pathogenic (Apr 01, 2018)	no assertion criteria provided Method: research	Macular dystrophy Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926653.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Pathogenic (Apr 06, 2021)	no assertion criteria provided Method: curation	not provided Affected status: yes Allele origin: germline	Leiden Open Variation Database Accession: SCV001744961.1 First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021	Publications: PubMed (11) PubMed: 8302543‚ 8485576‚ 9443872‚ 10532447‚ 19038374‚ 19243827‚ 22003107‚ 25082885‚ 28559085‚ 29555955‚ 32531846 Comment: Curator: Global Variome, with Curator vacancy. Submitters to LOVD: LOVD, Manon Peeters.
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001923785.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	Retina International Accession: SCV000117118.1 First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 Comment: http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_RDS:c.515G>A
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Comment:

The variant NM_000322.4:c.515G>A in the PRPH2 gene has been previously studied(PMIDs 8485576, 22003107, 25082885, 27977834, 28559085, 29555955). 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 (rs61755793,CM930637). It is present in gnomAD browser (AF 0.00000406). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.515G>A in the PRPH2 gene as a Pathogenic mutation.

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 172 of the PRPH2 protein (p.Arg172Gln). This variant is present in population databases (rs61755793, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant macular dystrophy or central areolar choroidal dystrophy in families, albeit with incomplete penetrance (PMID: 8485576, 19038374, 19243827). It has also been observed to segregate with disease in related individuals. This variant is also known as RDS p.Arg172Gln. ClinVar contains an entry for this variant (Variation ID: 13167). 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genotype-phenotype associations in a large PRPH2-related retinopathy cohort.	Reeves MJ	Human mutation	2020	PMID: 32531846
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.	Jespersgaard C	Scientific reports	2019	PMID: 30718709
Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.	Birtel J	Scientific reports	2018	PMID: 29555955
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.	Stone EM	Ophthalmology	2017	PMID: 28559085
Molecular diagnostic testing by eyeGENE: analysis of patients with hereditary retinal dystrophy phenotypes involving central vision loss.	Alapati A	Investigative ophthalmology & visual science	2014	PMID: 25082885
Central areolar choroidal dystrophy (CACD) and age-related macular degeneration (AMD): differentiating characteristics in multimodal imaging.	Smailhodzic D	Investigative ophthalmology & visual science	2011	PMID: 22003107
Central areolar choroidal dystrophy.	Boon CJ	Ophthalmology	2009	PMID: 19243827
Phenotypic variability and long-term follow-up of patients with known and novel PRPH2/RDS gene mutations.	Renner AB	American journal of ophthalmology	2009	PMID: 19038374
Clinical features of codon 172 RDS macular dystrophy: similar phenotype in 12 families.	Downes SM	Archives of ophthalmology (Chicago, Ill. : 1960)	1999	PMID: 10532447
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	American journal of human genetics	1998	PMID: 9443872
Macular dystrophy associated with mutations at codon 172 in the human retinal degeneration slow gene.	Wroblewski JJ	Ophthalmology	1994	PMID: 8302543
Mutations in the human retinal degeneration slow (RDS) gene can cause either retinitis pigmentosa or macular dystrophy.	Wells J	Nature genetics	1993	PMID: 8485576
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Text-mined citations for rs61755793 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000322.5(PRPH2):c.515G>A (p.Arg172Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61755793 ...