Submissions for variant NM_000180.4(GUCY2D):c.2512C>T (p.Arg838Cys)

gnomAD frequency: 0.00001  dbSNP: rs61750172

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001065465	SCV001230423	pathogenic	Cone-rod dystrophy 6; Leber congenital amaurosis 1	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 838 of the GUCY2D protein (p.Arg838Cys). This variant is present in population databases (rs61750172, gnomAD 0.004%). This missense change has been observed in individuals with autosomal dominant cone-rod dystrophy (PMID: 9618177, 15175914, 26298565). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9355). 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 GUCY2D protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GUCY2D function (PMID: 11115851). This variant disrupts the p.Arg838 amino acid residue in GUCY2D. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11115851, 12552567, 26298565). 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.
Blueprint Genetics	RCV001074299	SCV001239872	pathogenic	Retinal dystrophy	2019-06-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000084862	SCV001248904	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	GUCY2D: PM2, PM5, PP1:Moderate, PS4:Moderate, PP3, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197374	SCV001368094	likely pathogenic	Choroidal dystrophy, central areolar, 1	2019-04-30	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376215	SCV001573282	pathogenic	Leber congenital amaurosis 1	2021-04-08	criteria provided, single submitter	research	The GUCY2D c.2512C>T variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM1, PS3, PP1. Based on this evidence we have classified this variant as Pathogenic.
GeneDx	RCV000084862	SCV001763874	pathogenic	not provided	2022-04-04	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a dominant negative effect with a higher activity compared to wild type (Tucker et al., 1999; Wilkie et al., 2000); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12552567, 29555955, 28559085, 26747767, 30588428, 31456290, 32811265, 32821499, 22183351, 11115851, 24875811, 15175914, 26298565, 24664689, 22194653, 10430891, 11565546, 9618177, 18487367, 17041576, 34048777, 33369172)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000009949	SCV002102459	pathogenic	Cone-rod dystrophy 6	2022-02-22	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS4, PM5_STR, PM1_SUP, PM2_SUP, PP3
3billion	RCV000009949	SCV002318831	pathogenic	Cone-rod dystrophy 6	2022-03-22	criteria provided, single submitter	clinical testing	The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 9618177, 15175914, 26298565). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 9618177, 26298565). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 11115851). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009357,VCV000811743, PMID:11565546,18487367,11565546). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.799>=0.6, 3CNET: 0.827>=0.75). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: []%)(total allele frequency: dMAF: 0.00447). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Suma Genomics	RCV000009949	SCV002605338	pathogenic	Cone-rod dystrophy 6		criteria provided, single submitter	clinical testing
OMIM	RCV000009949	SCV000030170	pathogenic	Cone-rod dystrophy 6	2003-02-01	no assertion criteria provided	literature only
Retina International	RCV000084862	SCV000116998	not provided	not provided		no assertion provided	not provided
Department of Ophthalmology and Visual Sciences Kyoto University	RCV000009949	SCV000172507	pathogenic	Cone-rod dystrophy 6		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000009949	SCV000804656	pathogenic	Cone-rod dystrophy 6	2016-09-01	no assertion criteria provided	clinical testing
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003042	SCV001161099	pathogenic	Cone dystrophy	2019-06-23	no assertion criteria provided	research
Genomics England Pilot Project, Genomics England	RCV000009949	SCV001760418	pathogenic	Cone-rod dystrophy 6		no assertion criteria provided	clinical testing