Submissions for variant NM_000322.5(PRPH2):c.828+3A>T

gnomAD frequency: 0.00001  dbSNP: rs281865373

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000085026	SCV000227094	pathogenic	not provided	2015-03-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000085026	SCV000490745	pathogenic	not provided	2023-04-10	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001047656	SCV001211626	pathogenic	PRPH2-related disorder	2025-01-20	criteria provided, single submitter	clinical testing	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.
Blueprint Genetics	RCV001073686	SCV001239241	pathogenic	Retinal dystrophy	2019-08-15	criteria provided, single submitter	clinical testing
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250344	SCV001424664	pathogenic	Stargardt disease	2020-01-07	criteria provided, single submitter	clinical testing	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.
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250345	SCV001424665	pathogenic	Choroideremia	2020-01-07	criteria provided, single submitter	clinical testing	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.
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250346	SCV001424666	pathogenic	Patterned dystrophy of the retinal pigment epithelium	2020-01-07	criteria provided, single submitter	clinical testing	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.
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250347	SCV001424667	pathogenic	Vitelliform macular dystrophy 2	2020-01-07	criteria provided, single submitter	clinical testing	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.
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250357	SCV001424685	pathogenic	Retinitis pigmentosa	2020-01-07	criteria provided, single submitter	clinical testing	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.
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250358	SCV001424686	pathogenic	Doyne honeycomb retinal dystrophy	2020-01-07	criteria provided, single submitter	clinical testing	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.
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV001250359	SCV001424687	pathogenic	Cone-rod dystrophy	2020-01-07	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001047656	SCV004222903	pathogenic	PRPH2-related disorder	2023-11-20	criteria provided, single submitter	clinical testing	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.
Retina International	RCV000085026	SCV000117162	not provided	not provided		no assertion provided	not provided
Leiden Open Variation Database	RCV000085026	SCV001745010	likely pathogenic	not provided	2021-05-27	no assertion criteria provided	curation	Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Julia Lopez, LOVD, Manon Peeters.
GenomeConnect - Invitae Patient Insights Network	RCV001047656	SCV001749590	not provided	PRPH2-related disorder		no assertion provided	phenotyping only	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.
Genomics England Pilot Project, Genomics England	RCV001542666	SCV001760180	likely pathogenic	Patterned macular dystrophy 1		no assertion criteria provided	clinical testing