chr17-8013918-C-T

Variant names:

• chr17-8013918-C-T
• rs61750168
• NM_000180.4:c.2302C>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4 PP1 PM2_Supporting PM3_Strong PP3_Moderate PS3_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000180.4(GUCY2D):c.2302C>T is a missense variant predicted to replace arginine with tryptophan at position p.768. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0002728, with 440 alleles / 1,612,990 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 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID:23035049) and in at least 6 probands with early-onset severe retinal dystrophy who were compound heterozygous, including 2 with either the NM_000180.4(GUCY2D):c.2516del (p.Thr839fs) or NM_000180.4(GUCY2D):c.1633C>T (p.Gln545Ter) variants suspected in trans (1 point, PMID:23035049, PMID:16505055), both of which have been previously classified as pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with onset at 3 months (1 pt), night blindness (0.5 pts), nystagmus (1 pt), and visual acuity limited to light perception (1 pt), which together are specific for GUCYD2-related recessive retinopathy (total 4 pts, PMID:16505055, PP4). 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:23035049, PP1). The computational predictor REVEL gives a score of 0.817, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on GUCY2D function (PP3_Moderate). The splicing impact predictor SpliceAI gives scores of 0.16 for donor loss and 0.15 for acceptor loss, which are below the ClinGen LCA/eoRD VCEP recommended threshold of 0.2 and do not strongly predict an impact on splicing. The variant exhibited ~0% enzymatic activity when co-expressed with GCAP1 or GCAP2 in a guanylate cyclase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PMID:23035049, PMID:33997691). The variant when co-expressed with GCAP1 and RD3 exhibited dispersal of GCAP1 and RD3 throughout the cell rather than proper localization to the plasma membrane, indicating failure of the variant to interact with either factor (PMID:33109612). The variant also showed reduced RD3 binding by western blot when co-immunoprecipitated by either anti-GUCY2D or anti-RD3 antibody (PMID:25477517, PS3_Supporting). 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: PS3_Supporting, PM2_Supporting, PM3_Strong, PP1, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226075/MONDO:0100453/167

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: GUCY2D NM_000180.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:16 O:1
• Conservation: PhyloP100: 5.75

Genes affected

GUCY2D (HGNC:4689): (guanylate cyclase 2D, retinal) This gene encodes a retina-specific guanylate cyclase, which is a member of the membrane guanylyl cyclase family. Like other membrane guanylyl cyclases, this enzyme has a hydrophobic amino-terminal signal sequence followed by a large extracellular domain, a single membrane spanning domain, a kinase homology domain, and a guanylyl cyclase catalytic domain. In contrast to other membrane guanylyl cyclases, this enzyme is not activated by natriuretic peptides. Mutations in this gene result in Leber congenital amaurosis and cone-rod dystrophy-6 diseases. [provided by RefSeq, Dec 2008]

ENSG00000279174 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2D	NM_000180.4	c.2302C>T	p.Arg768Trp	missense_variant	Exon 12 of 20	ENST00000254854.5	NP_000171.1
GUCY2D	XM_011523816.2	c.2302C>T	p.Arg768Trp	missense_variant	Exon 11 of 19		XP_011522118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5	c.2302C>T	p.Arg768Trp	missense_variant	Exon 12 of 20	1	NM_000180.4	ENSP00000254854.4
ENSG00000279174	ENST00000623126.1	n.2461G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000151 AC: 38 AN: 251318 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000283 AC: 413 AN: 1460752 Hom.: 1 Cov.: 31 AF XY: 0.000281 AC XY: 204 AN XY: 726742

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000362

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74372

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.000121

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leber congenital amaurosis 1 Pathogenic:5

Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 03, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (40 heterozygotes, 0 homozygotes). This variant has been described as a founder mutation in northwest European populations (PMID: 16505055). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 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 protein tyrosine and serine/threonine kinase domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The missense variant, p.(Arg768Gln) has been observed in two individuals with LCA (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in greater than ten individuals with LCA in both compound heterozygous and homozygous states (ClinVar, LOVD, PMID: 16505055). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PS3, PM2, PP1, PP3, PP4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 02, 2023	_x000D_ Criteria applied: PM3_STR, PS3_MOD, PM5, PM2_SUP, PP3 -

not provided Pathogenic:3 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 07, 2020	The GUCY2D c.2302C>T; p.Arg768Trp variant (rs61750168) is reported in the medical literature in several individuals and families with retinal disease in both the homozygous and compound heterozygous state (Peshenko 2010, Stunkel 2018, Thompson 2017, Yzer 2006, Zulliger 2015) The variant is reported as pathogenic or likely pathogenic in the ClinVar database (Variation ID: 98563) and is listed in the general population with an allele frequency of 0.014% (40/282,714 alleles) in the Genome Aggregation Database. The arginine at codon 768 is highly conserved, located in the catalytic domain, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In support of this prediction, this variant is defective in functional studies (Jacobsen 2013, Zulliger 2015). Considering available information, this variant is classified as pathogenic. References: Jacobson SG et al. Determining consequences of retinal membrane guanylyl cyclase (RetGC1) deficiency in human Leber congenital amaurosis en route to therapy: residual cone-photoreceptor vision correlates with biochemical properties of the mutants. Hum Mol Genet. 2013 Jan 1;22(1):168-83. Peshenko IV et al. Activation of retinal guanylyl cyclase RetGC1 by GCAP1: stoichiometry of binding and effect of new LCA-related mutations. Biochemistry. 2010 Feb 2;49(4):709-17. Stunkel ML et al. Expanded Retinal Disease Spectrum Associated With Autosomal Recessive Mutations in GUCY2D. Am J Ophthalmol. 2018 Jun;190:58-68. Thompson JA et al. The genetic profile of Leber congenital amaurosis in an Australian cohort. Mol Genet Genomic Med. 2017 Nov;5(6):652-667. Yzer S et al. Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2006 Mar;47(3):1167-76. Zulliger R et al. Impaired association of retinal degeneration-3 with guanylate cyclase-1 and guanylate cyclase-activating protein-1 leads to leber congenital amaurosis-1. J Biol Chem. 2015 Feb 6;290(6):3488-99. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2025	Observed with an additional variant in the GUCY2D gene in patients with Leber congenital amaurosis in published literature, although it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Yzer et al., 2006; Coppieters et al., 2012; Astuti et al., 2016; Thompson et al., 2017); Published functional studies demonstrate a damaging effect with reduction in GUCY2D enzyme activation in the presence of GCAP1, diminished binding to GCAP1, and altered GCAP1 co-localization (Peshenko et al., 2010); 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: 26253563, 18632300, 21602930, 20683928, 23035049, 25477517, 26626312, 31429209, 10766140, 16505055, 29178642, 29559409, 16272259, 34426522, 31589614, 31964843, 37734845, 20050595, 22261762, 31816670, 32865313, 34008892, 35314386, 36369640, 37327959, 37510321, 34048777, 35836572, 36460718, 33109612) -

Retinal dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 22, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2020	- -

Night blindness, congenital stationary, type1i Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 03, 2019

- -

GUCY2D-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2024

The GUCY2D c.2302C>T variant is predicted to result in the amino acid substitution p.Arg768Trp. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with Leber congenital amaurosis type 1 (LCA1) (for example, see Jacobson et al. 2013. PubMed ID: 23035049; Thompson et al. 2017. PubMed ID: 29178642; Stunkel et al. 2018. PubMed ID: 29559409). This variant has also been shown to co-segregate with disease in a Polish family (Skorczyk-Werner et al. 2022. PubMed ID: 36369640). In vitro functional studies have demonstrated that the p.Arg768Trp variant disrupts protein-protein interactions required for protein activation and proper intracellular localization, leading to a complete loss of function (Peshenko et al. 2010. PubMed ID: 20050595; Jacobson et al. 2013. PubMed ID: 23035049; Zulliger et al. 2015. PubMed ID: 25477517; Peshenko et al. 2020. PubMed ID: 33109612). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Of note, a different missense variant at the same amino acid position (p.Arg768Gln) has also been reported as disease-causing in LCA1 patients (Wiszniewski et al. 2011. PubMed ID: 21153841; Wang et al. 2015. PubMed ID: 26047050; Sharon et al. 2019. PubMed ID: 31456290). Taken together, the p.Arg768Trp variant is interpreted as pathogenic. -

Leber congenital amaurosis Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 08, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 768 of the GUCY2D protein (p.Arg768Trp). This variant is present in population databases (rs61750168, gnomAD 0.03%). This missense change has been observed in individual(s) with Leber congenital amaurosis (PMID: 16505055, 17724218, 23035049, 26253563, 26626312). 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: 98563). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 20050595, 25477517). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

GUCY2D-related recessive retinopathy Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen

Jan 30, 2025

NM_000180.4(GUCY2D):c.2302C>T is a missense variant predicted to replace arginine with tryptophan at position p.768. This variant is present in gnomAD v.4.1.0 at a total allele frequency of 0.0002728, with 440 alleles / 1,612,990 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 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 23035049) and in at least 6 probands with early-onset severe retinal dystrophy who were compound heterozygous, including 2 with either the NM_000180.4(GUCY2D):c.2516del (p.Thr839fs) or NM_000180.4(GUCY2D):c.1633C>T (p.Gln545Ter) variants suspected in trans (1 point, PMID: 23035049, PMID: 16505055), both of which have been previously classified as pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with onset at 3 months (1 pt), night blindness (0.5 pts), nystagmus (1 pt), and visual acuity limited to light perception (1 pt), which together are specific for GUCYD2-related recessive retinopathy (total 4 pts, PMID: 16505055, PP4). 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: 23035049, PP1). The computational predictor REVEL gives a score of 0.817, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on GUCY2D function (PP3_Moderate). The splicing impact predictor SpliceAI gives scores of 0.16 for donor loss and 0.15 for acceptor loss, which are below the ClinGen LCA/eoRD VCEP recommended threshold of 0.2 and do not strongly predict an impact on splicing. The variant exhibited ~0% enzymatic activity when co-expressed with GCAP1 or GCAP2 in a guanylate cyclase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PMID: 23035049, PMID: 33997691). The variant when co-expressed with GCAP1 and RD3 exhibited dispersal of GCAP1 and RD3 throughout the cell rather than proper localization to the plasma membrane, indicating failure of the variant to interact with either factor (PMID: 33109612). The variant also showed reduced RD3 binding by western blot when co-immunoprecipitated by either anti-GUCY2D or anti-RD3 antibody (PMID: 25477517, PS3_Supporting). 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: PS3_Supporting, PM2_Supporting, PM3_Strong, PP1, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 01/22/2025). -

Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1;C4551884:Choroidal dystrophy, central areolar, 1;C5231408:Night blindness, congenital stationary, type1i Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 03, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.4	H
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.97
MPC		0.85
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61750168; hg19: chr17-7917236;