Submissions for variant NM_000180.4(GUCY2D):c.2513G>A (p.Arg838His)

dbSNP: rs61750173

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000009951	SCV000680254	pathogenic	Cone-rod dystrophy 6	2017-12-07	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000504851	SCV001240814	pathogenic	Retinal dystrophy	2018-11-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000084863	SCV001248905	pathogenic	not provided	2018-04-01	criteria provided, single submitter	clinical testing
Invitae	RCV001228516	SCV001400917	pathogenic	Cone-rod dystrophy 6; Leber congenital amaurosis 1	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 838 of the GUCY2D protein (p.Arg838His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant cone-rod dystrophy (PMID: 12552567, 26298565). It has also been observed to segregate with disease in related individuals. This variant is also known as 2586G>A. ClinVar contains an entry for this variant (Variation ID: 9357). 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. 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, 24875811, 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000084863	SCV001447772	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
MNM Diagnostics	RCV001271114	SCV001451958	pathogenic	Visual impairment; Macular dystrophy	2019-07-31	criteria provided, single submitter	clinical testing	According to ACMG Guidelines, the variant meets the following evidence of pathogenicity: PS1, PS2, PS3, PP1, PM2, PP5.
Institute of Medical Molecular Genetics, University of Zurich	RCV000009951	SCV001548155	likely pathogenic	Cone-rod dystrophy 6	2021-01-30	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV000009951	SCV001760419	pathogenic	Cone-rod dystrophy 6		criteria provided, single submitter	clinical testing
GeneDx	RCV000084863	SCV001765959	pathogenic	not provided	2022-04-05	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); Published functional studies suggest a damaging effect (dominant negative effect with a higher activity compared to wild type) (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: 28041643, 25082885, 23563732, 18487367, 22183351, 22968130, 24480840, 11115851, 25283059, 24875811, 15175914, 26298565, 29061346, 28181551, 25515582, 10676808, 11565546, 22194653, 29555955, 31456290, 32821499, 32036094, 32581362, 34048777, 32811265, 12552567, 33691693)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000009951	SCV001950061	pathogenic	Cone-rod dystrophy 6	2021-04-07	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001723556	SCV001950280	pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Arg838His variant in GUCY2D was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PS3, PM1, PP1. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV003324497	SCV004030413	pathogenic	Cone-rod dystrophy	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
OMIM	RCV000009951	SCV000030172	pathogenic	Cone-rod dystrophy 6	2003-02-01	no assertion criteria provided	literature only
Retina International	RCV000084863	SCV000116999	not provided	not provided		no assertion provided	not provided
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504851	SCV000598721	likely pathogenic	Retinal dystrophy	2015-01-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000009951	SCV000804657	pathogenic	Cone-rod dystrophy 6	2016-09-01	no assertion criteria provided	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787614	SCV000926598	uncertain significance	Progressive cone dystrophy (without rod involvement)	2018-04-01	no assertion criteria provided	research
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003043	SCV001161100	pathogenic	Cone dystrophy	2019-06-23	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000084863	SCV001955988	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000084863	SCV001969079	pathogenic	not provided		no assertion criteria provided	clinical testing