Submissions for variant NM_000180.4(GUCY2D):c.1343C>A (p.Ser448Ter)

dbSNP: rs61749679

Total submissions: 9

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	RCV005053890	SCV005687758	pathogenic	GUCY2D-related recessive retinopathy	2025-01-31	reviewed by expert panel	curation	NM_000180.4(GUCY2D):c.1343C>A (p.Ser448Ter) is a nonsense variant that introduces a premature stop codon into exon 4 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 0.00001242, with 20 alleles / 1610586 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) during the first year of life (1 pt), as well as nystagmus (1 pt), non-recordable electroretinogram responses from both rods (0.5 pts) and cones (1 pt), and normal fundus, which together are specific for GUCY2D-related recessive retinopathy (total 4 points, PMID: 10951519, 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).
Mendelics	RCV000989737	SCV001140281	pathogenic	Cone-rod dystrophy 6	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001037164	SCV001200564	pathogenic	Cone-rod dystrophy 6; Leber congenital amaurosis 1	2024-12-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser448*) 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 (rs61749679, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis (PMID: 10951519). ClinVar contains an entry for this variant (Variation ID: 98540). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000084831	SCV001248901	pathogenic	not provided	2016-10-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000084831	SCV002576175	pathogenic	not provided	2022-09-21	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32531858, 10951519, 29548835, 32865313, 15024725)
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004815022	SCV005073366	pathogenic	Retinal dystrophy	2008-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005025142	SCV005652768	pathogenic	Choroidal dystrophy, central areolar, 1; Cone-rod dystrophy 6; Leber congenital amaurosis 1; Night blindness, congenital stationary, type1i	2024-05-15	criteria provided, single submitter	clinical testing
Retina International	RCV000084831	SCV000116967	not provided	not provided		no assertion provided	not provided
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV001250830	SCV001426317	pathogenic	Leber congenital amaurosis 1		no assertion criteria provided	research