ClinVar Miner

Submissions for variant NM_000180.4(GUCY2D):c.2516del (p.Thr839fs)

gnomAD frequency: 0.00003  dbSNP: rs756044745
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen RCV005053974 SCV005687759 pathogenic GUCY2D-related recessive retinopathy 2025-01-31 reviewed by expert panel curation NM_000180.4(GUCY2D):c.2516del (p.Thr839ArgfsTer27) is a frameshift variant that introduces a premature stop codon into exon 13 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.00002604, with 42 alleles / 1613212 total alleles , which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), flat ERG responses from rods (0.5 pts) and cones (1 pt), nystagmus (1 pt), and reduced visual acuity (1 pt), which together are specific for GUCY2D-related recessive retinopathy (4 pts total, PMID: 29178642, PP4). In summary, this variant meets the criteria to be classified as pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025).
Labcorp Genetics (formerly Invitae), Labcorp RCV001207599 SCV001378961 pathogenic Cone-rod dystrophy 6; Leber congenital amaurosis 1 2022-03-10 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Thr839Argfs*27) in the GUCY2D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GUCY2D are known to be pathogenic (PMID: 10951519, 11328726). This variant is present in population databases (rs756044745, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis (PMID: 29178642). ClinVar contains an entry for this variant (Variation ID: 938393).

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