VCV000138908.8 - ClinVar

NM_000322.5(PRPH2):c.-11A>C

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.

(10)

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.

Benign

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.-11A>C

Variation ID: 138908 Accession: VCV000138908.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p21.1 6: 42722345 (GRCh38) [ NCBI UCSC ] 6: 42690083 (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	Oct 2, 2016	Jul 7, 2021	Jan 13, 2018

HGVS

Nucleotide	Protein	Molecular consequence
NM_000322.5:c.-11A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		5 prime UTR
NC_000006.12:g.42722345T>G
NC_000006.11:g.42690083T>G
NG_009176.2:g.5276A>C

Protein change

Other names

Canonical SPDI

NC_000006.12:42722344:T:G

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

effect on translation; Variation Ontology [ VariO:0399]

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.

0.03554 (G)

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

Exome Aggregation Consortium (ExAC) 0.00998

The Genome Aggregation Database (gnomAD) 0.03391

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.03521

Trans-Omics for Precision Medicine (TOPMed) 0.03553

1000 Genomes Project 0.03554

1000 Genomes Project 30x 0.03701

The Genome Aggregation Database (gnomAD), exomes 0.00809

Links

ClinGen: CA293076 dbSNP: rs114062933 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.
not specified	Benign (3)	criteria provided, multiple submitters, no conflicts	Aug 8, 2011	RCV000127758.8
Retinitis pigmentosa	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000289578.6
Cone-rod dystrophy	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000292322.6
Choroidal dystrophy, central areolar 2	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000348039.6
Pigmentary retinal dystrophy	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000344526.6
Patterned macular dystrophy 1	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000408099.6
Adult-onset foveomacular vitelliform dystrophy	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000383991.6
not provided	not provided (1)	no classification provided	-	RCV000767336.2

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.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000303591.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Aug 08, 2011)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000171337.10 First in ClinVar: Jun 23, 2014 Last updated: Oct 02, 2016	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Cone-rod dystrophy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000463295.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Pigmentary retinal dystrophy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000463299.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Vitelliform macular dystrophy 3 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000463297.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Patterned macular dystrophy 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000463300.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Retinitis pigmentosa Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000463298.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Choroidal dystrophy, central areolar 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000463296.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Apr 06, 2021)	no assertion criteria provided Method: curation	not specified Affected status: yes Allele origin: germline	Leiden Open Variation Database Accession: SCV001745016.1 First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021	Publications: PubMed (1) PubMed: 17698758 Comment: Curator: Global Variome, with Curator vacancy. Submitter to LOVD: Manon Peeters.
not provided (-)	no classification provided Method: in vitro	not provided Affected status: not applicable Allele origin: not applicable	Seelig Lab, University of Washington Accession: SCV000897908.1 First in ClinVar: Apr 17, 2019 Last updated: Apr 17, 2019	Other databases https://www.biorxiv.org/content/… https://www.biorxiv.org/content/10.1101/310375v1 Method: HEK293T cells were plated on 10 cm cell culture dishes 24 hours before transfection (1 - 2 million per plate). At 60% to 80% confluency, cells were transfected with 14.5 micrograms of library mRNA using Lipofectamine MessengerMAX (Thermo Fisher Scientific) following the manufacturer's protocol. Plates were washed with 10 ml 1x DBPS and 10 ml media (DMEM with 10% FBS and 1% Penicillin-Streptomycin) after one hour of incubation. Cells were lysed 12 hours after transfection. After 12 hours of growth at 37 degrees C, cells were placed on ice and media was aspirated. Translating ribosomes were halted by adding 5 ml of wash buffer and were then placed at 37 degrees C for 5 minutes followed by aspiration on ice. Washed by adding 5 ml wash buffer and aspirating thoroughly. Added 300 microliters of ice-cold lysis buffer, scraped cells, broke up cell clumps by pipetting ~5 times, and then placed suspended cells into a pre-chilled microcentrifuge tube. Let sit for 10 minutes on ice and then triturated by passing through a 25-G needle 10 times. Spun at 16,000 x g for 5 minutes to pellet cell debris and nuclei. Saved supernatant and added 1.5 microliters of 1 U/microliter DNase I (final concentration of 0.005 U/microliter) and placed on ice for 30 minutes. Either stored at -80 degrees C or proceeded directly to polysome profiling. Result: Significant log2 change in mean ribosome load: 0.59

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
effect on translation (VariO:0399)	HEK293T cells were plated on 10 cm cell culture dishes 24 hours before transfection (1 - 2 million per plate). At 60% to 80% confluency, cells were transfected with 14.5 micrograms of library mRNA using Lipofectamine MessengerMAX (Thermo Fisher Scientific) following the manufacturer's protocol. Plates were washed with 10 ml 1x DBPS and 10 ml media (DMEM with 10% FBS and 1% Penicillin-Streptomycin) after one hour of incubation. Cells were lysed 12 hours after transfection. After 12 hours of growth at 37 degrees C, cells were placed on ice and media was aspirated. Translating ribosomes were halted by adding 5 ml of wash buffer and were then placed at 37 degrees C for 5 minutes followed by aspiration on ice. Washed by adding 5 ml wash buffer and aspirating thoroughly. Added 300 microliters of ice-cold lysis buffer, scraped cells, broke up cell clumps by pipetting ~5 times, and then placed suspended cells into a pre-chilled microcentrifuge tube. Let sit for 10 minutes on ice and then triturated by passing through a 25-G needle 10 times. Spun at 16,000 x g for 5 minutes to pellet cell debris and nuclei. Saved supernatant and added 1.5 microliters of 1 U/microliter DNase I (final concentration of 0.005 U/microliter) and placed on ice for 30 minutes. Either stored at -80 degrees C or proceeded directly to polysome profiling.	Significant log2 change in mean ribosome load: 0.59	Seelig Lab, University of Washington Accession: SCV000897908.1	Other databases https://www.biorxiv.org/content/…

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical and genetic heterogeneity in multifocal vitelliform dystrophy.	Boon CJ	Archives of ophthalmology (Chicago, Ill. : 1960)	2007	PMID: 17698758
https://www.biorxiv.org/content/10.1101/310375v1	-	-	-	-

Text-mined citations for rs114062933 ...

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 Sep 17, 2024

ClinVar Genomic variation as it relates to human health

NM_000322.5(PRPH2):c.-11A>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs114062933 ...