Submissions for variant NM_000180.4(GUCY2D):c.935C>T (p.Thr312Met)

gnomAD frequency: 0.00003  dbSNP: rs61749673

Total submissions: 6

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	RCV005053904	SCV005687745	likely pathogenic	GUCY2D-related recessive retinopathy	2025-01-30	reviewed by expert panel	curation	The NM_000180.4(GUCY2D):c.935C>T (p.Thr312Met) variant is predicted to replace the threonine at position p.312 with methionine. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.000005599, with 9 alleles / 1,607,292 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). The computational predictor REVEL gives a score of 0.794, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RetGC-1 protein function (PP3_Moderate). This variant has been reported in at least 5 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous for the variant. The patient reported in PMID #19959640 has the p.Arg795Trp variant, unclassified by the LCA/eoRD VCEP, suspected in trans (not counted). The patient reported in PMID #26047050 has the p.Arg332Pro variant, currently unclassified, confirmed in trans (0.25 pts). The 2 unrelated patients reported in PMIDs #27375279 and #27422788 both have the p.Leu251Pro variant, currently unclassified, confirmed in trans (0.5 pts). The patient reported in PMID #27375279 has the p.Ser1007Leu variant, currently unclassified, confirmed in trans (0.25 points) (1 total point, PM3). At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts) before age 1 (1 pt), nystagmus (1 pt), poor vision (1 pt), extinguished rod and cone ERGs (1.5 pts), attenuated vessels (0.5 pts) and no foveal reflex which together are specific for GUCY2D-related recessive retinopathy (total 5.5 points, PMID: 21602930, PP4). In summary, this variant meets the criteria to be classified as Likely Pathogenic for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP3_Moderate, PP4, PM3. (VCEP specifications version 1.0.0; date of approval 01/22/2025).
GeneDx	RCV000084906	SCV001986109	uncertain significance	not provided	2024-11-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15691574, 26047050, 20079931, 21602930, 26253563, 27375279, 27422788, 34048777, 17964524, 19959640, 31964843, 16205573, 29061346)
3billion, Medical Genetics	RCV001250818	SCV002572926	likely pathogenic	Leber congenital amaurosis 1	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.60). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GUCY2D-related disorder (ClinVar ID: VCV000098610 / PMID: 15691574 , 26047050 / 3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset). Different missense changes at the same codon (p.Thr312Arg, p.Thr312Pro) have been reported to be associated with GUCY2D-related disorder (PMID: 17964524 , 26047050). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003764783	SCV004593105	likely pathogenic	Cone-rod dystrophy 6; Leber congenital amaurosis 1	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 312 of the GUCY2D protein (p.Thr312Met). This variant is present in population databases (rs61749673, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive GUCY2D-related conditions (PMID: 15691574, 16205573, 19959640, 31964843, 34048777). ClinVar contains an entry for this variant (Variation ID: 98610). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GUCY2D protein function. This variant disrupts the p.Thr312 amino acid residue in GUCY2D. Other variant(s) that disrupt this residue have been observed in individuals with GUCY2D-related conditions (PMID: 26047050), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Retina International	RCV000084906	SCV000117042	not provided	not provided		no assertion provided	not provided
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV001250818	SCV001426303	likely pathogenic	Leber congenital amaurosis 1		no assertion criteria provided	research