ClinVar Miner

Submissions for variant NM_000322.5(PRPH2):c.623G>A (p.Gly208Asp)

gnomAD frequency: 0.00010  dbSNP: rs139185976
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001051123 SCV001215261 pathogenic PRPH2-related disorder 2024-01-06 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 208 of the PRPH2 protein (p.Gly208Asp). This variant is present in population databases (rs139185976, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant retinal disease (PMID: 9279751, 12042139, 21071739, 25447119, 29555955). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 437965). 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) performed at Invitae indicates that this missense variant is expected to disrupt PRPH2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074827 SCV001240427 likely pathogenic Retinal dystrophy 2019-07-17 criteria provided, single submitter clinical testing
NEI Ophthalmic Genomics Laboratory, National Institutes of Health RCV001250285 SCV001424597 likely pathogenic Stargardt disease 2020-01-07 criteria provided, single submitter clinical testing The variant NM_000322.4:c.623G>A in the PRPH2 gene has been previously studied(PMIDs 9279751, 12042139, 25447119, 29555955). We found this variant in 1 patient(s) in a PRPH2 cohort study (Reeves et al. 2020). This variant is listed in dbSNP and/or HGMD (rs139185976,CM971288). It is present in gnomAD browser (AF 0.0000487). It is not enriched in the PRPH2 disease cohort. We invoked ACMG criteria [PP1-M, PM1, PM2, PP3, PP5] and classified NM_000322.4:c.623G>A in the PRPH2 gene as a Likely Pathogenic mutation.
GeneDx RCV001530240 SCV001803209 uncertain significance not provided 2020-01-03 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31589614, 32531846, 32581362, 21071739, 17653047, 30726412, 30718709, 28041643, 29555955, 9279751, 25447119, 12042139)
Mendelics RCV002248741 SCV002518912 pathogenic Pigmentary retinal dystrophy 2022-05-04 criteria provided, single submitter clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504827 SCV000598701 likely pathogenic Macular dystrophy 2015-01-01 no assertion criteria provided research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000504827 SCV000926654 pathogenic Macular dystrophy 2018-04-01 no assertion criteria provided research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000787665 SCV000926655 pathogenic Patterned macular dystrophy 1 2018-04-01 no assertion criteria provided research
Leiden Open Variation Database RCV001530240 SCV001744981 likely pathogenic not provided 2021-04-06 no assertion criteria provided curation Curator: Global Variome, with Curator vacancy. Submitters to LOVD: Global Variome, with Curator vacancy, LOVD, Manon Peeters.
PreventionGenetics, part of Exact Sciences RCV001051123 SCV005361593 likely pathogenic PRPH2-related disorder 2024-05-26 no assertion criteria provided clinical testing The PRPH2 c.623G>A variant is predicted to result in the amino acid substitution p.Gly208Asp. This variant has been reported many times in individuals with autosomal dominant retinal disease, and in some cases was found to segregate with disease in kindreds (see for examples: pedigree Bu, Kohl et al. 1997. PubMed ID: 9279751; Manes et al. 2014. PubMed ID: 25447119; Table S1, Birtel et al. 2018. PubMed ID: 29555955; Supplemental Table, Holtan et al. 2019. PubMed ID: 31429209; Table S2, Zampaglione et al. 2020. PubMed ID: 32037395; Table S1, Weisschuh et al. 2020. PubMed ID: 32531858). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.

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