ClinVar Genomic variation as it relates to human health
NM_000322.5(PRPH2):c.828+3A>T
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000322.5(PRPH2):c.828+3A>T
Variation ID: 98713 Accession: VCV000098713.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p21.1 6: 42704362 (GRCh38) [ NCBI UCSC ] 6: 42672100 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Feb 14, 2024 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000322.5:c.828+3A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000006.12:g.42704362T>A NC_000006.11:g.42672100T>A NG_009176.2:g.23259A>T - Protein change
- Other names
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- Canonical SPDI
- NC_000006.12:42704361:T:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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 | ||
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HI score
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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. |
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PRPH2 | - | - |
GRCh38 GRCh37 |
744 | 756 |
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. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 10, 2023 | RCV000085026.11 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 26, 2024 | RCV001047656.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 15, 2019 | RCV001073686.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 7, 2020 | RCV001250345.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 7, 2020 | RCV001250359.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 7, 2020 | RCV001250357.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 7, 2020 | RCV001250344.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 7, 2020 | RCV001250358.2 | |
Likely pathogenic (1) |
no assertion criteria provided
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- | RCV001542666.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 7, 2020 | RCV001250346.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 7, 2020 | RCV001250347.2 | |
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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. |
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Pathogenic
(Mar 26, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000227094.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Aug 15, 2019)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001239241.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
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Pathogenic
(Jan 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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Vitelliform macular dystrophy 2
Affected status: yes
Allele origin:
germline
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NEI Ophthalmic Genomics Laboratory, National Institutes of Health
Accession: SCV001424667.1
First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020 |
Comment:
The variant NM_000322.4:c.828+3A>T in the PRPH2 gene has been previously studied(PMIDs 11139241, 11704030, 25675413, 25525159, 26842753). We found this variant in 36 patient(s) in a … (more)
The variant NM_000322.4:c.828+3A>T in the PRPH2 gene has been previously studied(PMIDs 11139241, 11704030, 25675413, 25525159, 26842753). We found this variant in 36 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs281865373,CS010139). It is present in gnomAD browser (AF 0.00000429). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM2, PP3, PP5] and classified NM_000322.4:c.828+3A>T in the PRPH2 gene as a Pathogenic mutation. (less)
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Pathogenic
(Jan 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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Patterned dystrophy of the retinal pigment epithelium
Affected status: yes
Allele origin:
germline
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NEI Ophthalmic Genomics Laboratory, National Institutes of Health
Accession: SCV001424666.1
First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020 |
Comment:
The variant NM_000322.4:c.828+3A>T in the PRPH2 gene has been previously studied(PMIDs 11139241, 11704030, 25675413, 25525159, 26842753). We found this variant in 36 patient(s) in a … (more)
The variant NM_000322.4:c.828+3A>T in the PRPH2 gene has been previously studied(PMIDs 11139241, 11704030, 25675413, 25525159, 26842753). We found this variant in 36 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs281865373,CS010139). It is present in gnomAD browser (AF 0.00000429). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM2, PP3, PP5] and classified NM_000322.4:c.828+3A>T in the PRPH2 gene as a Pathogenic mutation. (less)
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Pathogenic
(Jan 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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Stargardt disease
Affected status: yes
Allele origin:
germline
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NEI Ophthalmic Genomics Laboratory, National Institutes of Health
Accession: SCV001424664.1
First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020 |
Comment:
The variant NM_000322.4:c.828+3A>T in the PRPH2 gene has been previously studied(PMIDs 11139241, 11704030, 25675413, 25525159, 26842753). We found this variant in 36 patient(s) in a … (more)
The variant NM_000322.4:c.828+3A>T in the PRPH2 gene has been previously studied(PMIDs 11139241, 11704030, 25675413, 25525159, 26842753). We found this variant in 36 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs281865373,CS010139). It is present in gnomAD browser (AF 0.00000429). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM2, PP3, PP5] and classified NM_000322.4:c.828+3A>T in the PRPH2 gene as a Pathogenic mutation. (less)
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Pathogenic
(Jan 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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Choroideremia
Affected status: yes
Allele origin:
germline
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NEI Ophthalmic Genomics Laboratory, National Institutes of Health
Accession: SCV001424665.1
First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020 |
Comment:
The variant NM_000322.4:c.828+3A>T in the PRPH2 gene has been previously studied(PMIDs 11139241, 11704030, 25675413, 25525159, 26842753). We found this variant in 36 patient(s) in a … (more)
The variant NM_000322.4:c.828+3A>T in the PRPH2 gene has been previously studied(PMIDs 11139241, 11704030, 25675413, 25525159, 26842753). We found this variant in 36 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs281865373,CS010139). It is present in gnomAD browser (AF 0.00000429). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM2, PP3, PP5] and classified NM_000322.4:c.828+3A>T in the PRPH2 gene as a Pathogenic mutation. (less)
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Pathogenic
(Jan 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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Doyne honeycomb retinal dystrophy
Affected status: yes
Allele origin:
germline
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NEI Ophthalmic Genomics Laboratory, National Institutes of Health
Accession: SCV001424686.1
First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020 |
Comment:
The variant NM_000322.4:c.828+3A>T in the PRPH2 gene has been previously studied(PMIDs 11139241, 11704030, 25675413, 25525159, 26842753). We found this variant in 36 patient(s) in a … (more)
The variant NM_000322.4:c.828+3A>T in the PRPH2 gene has been previously studied(PMIDs 11139241, 11704030, 25675413, 25525159, 26842753). We found this variant in 36 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs281865373, CS010139). It is present in gnomAD browser (AF 0.00000429). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM2, PP3, PP5] and classified NM_000322.4:c.828+3A>T in the PRPH2 gene as a Pathogenic mutation. (less)
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Pathogenic
(Jan 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa
Affected status: yes
Allele origin:
germline
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NEI Ophthalmic Genomics Laboratory, National Institutes of Health
Accession: SCV001424685.1
First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020 |
Comment:
The variant NM_000322.4:c.828+3A>T in the PRPH2 gene has been previously studied(PMIDs 11139241, 11704030, 25675413, 25525159, 26842753). We found this variant in 36 patient(s) in a … (more)
The variant NM_000322.4:c.828+3A>T in the PRPH2 gene has been previously studied(PMIDs 11139241, 11704030, 25675413, 25525159, 26842753). We found this variant in 36 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs281865373,CS010139). It is present in gnomAD browser (AF 0.00000429). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM2, PP3, PP5] and classified NM_000322.4:c.828+3A>T in the PRPH2 gene as a Pathogenic mutation. (less)
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Pathogenic
(Jan 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cone-rod dystrophy
Affected status: yes
Allele origin:
germline
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NEI Ophthalmic Genomics Laboratory, National Institutes of Health
Accession: SCV001424687.1
First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020 |
Comment:
The variant NM_000322.4:c.828+3A>T in the PRPH2 gene has been previously studied(PMIDs 11139241, 11704030, 25675413, 25525159, 26842753). We found this variant in 36 patient(s) in a … (more)
The variant NM_000322.4:c.828+3A>T in the PRPH2 gene has been previously studied(PMIDs 11139241, 11704030, 25675413, 25525159, 26842753). We found this variant in 36 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs281865373, CS010139). It is present in gnomAD browser (AF 0.00000429). It is enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PS4, PP1-S, PM2, PP3, PP5] and classified NM_000322.4:c.828+3A>T in the PRPH2 gene as a Pathogenic mutation. (less)
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Pathogenic
(Nov 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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PRPH2-Related Disorders
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004222903.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: PRPH2 c.828+3A>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: PRPH2 c.828+3A>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: four predict the variant weakens a canonical 5' donor site. The variant allele was found at a frequency of 8.4e-06 in 238042 control chromosomes (gnomAD). At least one study reports experimental evidence supporting this prediction, finding aberantly spliced transcripts in affected individuals (Shankar_2015). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.828+3A>T has been reported in the literature in many individuals affected with retinal degeneration including retinitis pigmentosa (Sullivan_2006, Shankar_2015, Reeves_2020). These reports suggest the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16799052, 32531846, 25675413). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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PRPH2-Related Disorders
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001211626.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 2 of the PRPH2 gene. It does not directly change the encoded amino acid sequence of the PRPH2 protein. … (more)
This sequence change falls in intron 2 of the PRPH2 gene. It does not directly change the encoded amino acid sequence of the PRPH2 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs281865373, gnomAD 0.001%). This variant has been observed in individuals with autosomal dominant retinal disease in many families and may be a founder variant (PMID: 11139241, 25675413, 26842753). It is commonly reported in individuals of European ancestry (PMID: 11139241, 25675413, 26842753). This variant is also known as RDS IVS2+3A>T. ClinVar contains an entry for this variant (Variation ID: 98713). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in inclusion of part of intron 2 and introduces a new termination codon (PMID: 25675413). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000490745.5
First in ClinVar: Feb 20, 2014 Last updated: Apr 23, 2023 |
Comment:
Published functional studies demonstrate abnormal gene splicing (Shankar et al., 2015); In silico analysis supports a deleterious effect on splicing; This variant is associated with … (more)
Published functional studies demonstrate abnormal gene splicing (Shankar et al., 2015); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 11704030, 32531846, 25525159, 25082885, 11139241, 20861475, 32037395, 34758253, 25675413, 26842753) (less)
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Likely pathogenic
(May 27, 2021)
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no assertion criteria provided
Method: curation
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not provided
Affected status: yes
Allele origin:
germline
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Leiden Open Variation Database
Accession: SCV001745010.1
First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021 |
Comment:
Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Julia Lopez, LOVD, Manon Peeters.
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Patterned macular dystrophy 1
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760180.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Retina International
Accession: SCV000117162.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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PRPH2-Related Disorders
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749590.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Pathogenic and reported on 10-29-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpreted as Pathogenic and reported on 10-29-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Abnormality of vision (present) , Myopia (present) , Abnormal retinal morphology (present) , Anxiety (present) , Bipolar affective disorder (present) , Depression (present)
Indication for testing: Diagnostic
Age: 30-39 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-10-29
Testing laboratory interpretation: Pathogenic
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genotype-phenotype associations in a large PRPH2-related retinopathy cohort. | Reeves MJ | Human mutation | 2020 | PMID: 32531846 |
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. | Stone EM | Ophthalmology | 2017 | PMID: 28559085 |
Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, in PRPH2 and Protein Haplotypes in trans as Modifiers. | Shankar SP | Investigative ophthalmology & visual science | 2016 | PMID: 26842753 |
Founder Effect of a c.828+3A>T Splice Site Mutation in Peripherin 2 (PRPH2) Causing Autosomal Dominant Retinal Dystrophies. | Shankar SP | JAMA ophthalmology | 2015 | PMID: 25675413 |
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 |
Prevalence of mutations in eyeGENE probands with a diagnosis of autosomal dominant retinitis pigmentosa. | Sullivan LS | Investigative ophthalmology & visual science | 2013 | PMID: 23950152 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Prevalence of disease-causing mutations in families with autosomal dominant retinitis pigmentosa: a screen of known genes in 200 families. | Sullivan LS | Investigative ophthalmology & visual science | 2006 | PMID: 16799052 |
Genetic and phenotypic heterogeneity in pattern dystrophy. | Francis PJ | The British journal of ophthalmology | 2005 | PMID: 16113362 |
Splice site mutation in the peripherin/RDS gene associated with pattern dystrophy of the retina. | Sears JE | American journal of ophthalmology | 2001 | PMID: 11704030 |
Prevalence of mutations causing retinitis pigmentosa and other inherited retinopathies. | Sohocki MM | Human mutation | 2001 | PMID: 11139241 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PRPH2 | - | - | - | - |
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Text-mined citations for rs281865373 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.