Submissions for variant NM_000180.4(GUCY2D):c.307G>A (p.Glu103Lys)

gnomAD frequency: 0.00004  dbSNP: rs61749668

Total submissions: 11

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	RCV005053900	SCV005687718	likely pathogenic	GUCY2D-related recessive retinopathy	2025-01-30	reviewed by expert panel	curation	NM_000180.4(GUCY2D):c.307G>A (p.Glu103Lys) is a missense variant that is predicted to replace glutamic acid with lysine at position p.103. Another missense variant in the same codon, NM_000180.4(GUCY2D):c.308A>T (p.Glu103Val), has been reported in association with GUCY2D-related recessive retinopathy (PMID: 21602930), and splicing prediction using SpliceAI did not strongly predict an effect on splicing due to either of these variants. However, this second variant has not yet been classified by the ClinGen LCA / eoRD VCEP, so PM5 is not met. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0001749, with 257 alleles / 1,469,548 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). This variant has been reported in at least 2 apparently unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_000180.4(GUCY2D):c.2595del (p.Lys866fs) variant or the NM_000180.4(GUCY2D):c.91dup (p.Arg31fs) variant confirmed in trans, which were previously classified pathogenic by the ClinGen LCA/eoRD VCEP (2 points, PMID: 29178642, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 31704230, PP1). At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5 pts), nystagmus (1 pt), visual acuity limited to light perception (1 pt) since birth (1 pt), flat ERG responses from both rods (0.5 pts) and cones (1 pt), high hypermetropia, being drawn to bright light, sluggish pupillary responses (0.5 pts), eye poking, and normal appearing fundus with some abnormality in the reflection from the inner limiting membrane at high magnification, which together are specific for GUCY2D-related recessive retinopathy (total 5.5 points, PMID: 29178642, PP4). The computational predictor REVEL gives a score of 0.547, which is below the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RetGC-1 protein function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.00, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. 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, PM3_Strong, PP1 and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001053255	SCV001217506	pathogenic	Cone-rod dystrophy 6; Leber congenital amaurosis 1	2024-02-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 103 of the GUCY2D protein (p.Glu103Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive GUCY2D-related conditions (PMID: 28041643, 29178642; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 98590). 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 not expected to disrupt GUCY2D protein function with a negative predictive value of 80%. This variant disrupts the p.Glu103 amino acid residue in GUCY2D. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21602930, 34048777). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000084885	SCV002028010	likely pathogenic	not provided	2021-11-17	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: 17964524, 34048777, 32581362, 18055820, 31704230, 28041643, 29178642)
Genetics and Molecular Pathology, SA Pathology	RCV001250822	SCV002556853	likely pathogenic	Leber congenital amaurosis 1	2020-06-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689453	SCV005185633	pathogenic	Leber congenital amaurosis	2024-05-16	criteria provided, single submitter	clinical testing	Variant summary: GUCY2D c.307G>A (p.Glu103Lys) results in a conservative amino acid change located in the Receptor, ligand binding region (IPR001828) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.307G>A has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis (example, Bouzia_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Additionally, at least one variant at the Glu103 residue has been reported as associated with disease in ClinVar (p.Glu103Val), suggesting that this codon is functionally important. These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 31704230). ClinVar contains an entry for this variant (Variation ID: 98590). Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001250822	SCV005398431	pathogenic	Leber congenital amaurosis 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function variants are associated with Leber congenital amaurosis 1 (LCA, MIM#204000) and gain of function variants are associated with Cone-rod dystrophy 6 (MIM#601777). Gain of function variants tend to cluster in the linker domain specifically around p.838 (OMIM, PMIDs: 29061346, 11709018, 11115851). (I) 0108 - This gene is associated with both recessive and dominant disease. Heterozygotes with autosomal dominant disease tend to be less severely affected (OMIM, PMID: 29061346). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v3 <0.01 for a recessive condition (5 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated receptor family ligand binding region (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in over ten individuals with Leber congenital amaurosis (ClinVar, PMIDs: 31704230, 18055820, 28041643, 29178642). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005016379	SCV005652763	pathogenic	Choroidal dystrophy, central areolar, 1; Cone-rod dystrophy 6; Leber congenital amaurosis 1; Night blindness, congenital stationary, type1i	2024-05-17	criteria provided, single submitter	clinical testing
Retina International	RCV000084885	SCV000117021	not provided	not provided		no assertion provided	not provided
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505073	SCV000598722	likely pathogenic	Cone dystrophy	2015-01-01	no assertion criteria provided	research
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV001250822	SCV001426307	likely pathogenic	Leber congenital amaurosis 1		no assertion criteria provided	research
Genomics England Pilot Project, Genomics England	RCV001250822	SCV001760417	likely pathogenic	Leber congenital amaurosis 1		no assertion criteria provided	clinical testing