chr17-8013918-C-T

Position:

chr17-8013918-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5PP3_StrongPP5_Very_Strong

The NM_000180.4(GUCY2D):c.2302C>T(p.Arg768Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000273 in 1,612,990 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R768Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

GUCY2D
NM_000180.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 5.75

Variant links:

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]

GUCY2D links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-8013919-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 560463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

PP5

Variant 17-8013918-C-T is Pathogenic according to our data. Variant chr17-8013918-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 98563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8013918-C-T is described in Lovd as [Pathogenic]. Variant chr17-8013918-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-8013918-C-T is described in Lovd as [Likely_pathogenic]. Variant chr17-8013918-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUCY2D	NM_000180.4 linkuse as main transcript	c.2302C>T	p.Arg768Trp	missense_variant	12/20	ENST00000254854.5
GUCY2D	XM_011523816.2 linkuse as main transcript	c.2302C>T	p.Arg768Trp	missense_variant	11/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUCY2D	ENST00000254854.5 linkuse as main transcript	c.2302C>T	p.Arg768Trp	missense_variant	12/20	1	NM_000180.4	P1
	ENST00000623126.1 linkuse as main transcript	n.2461G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

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:

AN:

251318

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135866

show subpopulations

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.:

Cov.:

AF XY:

0.000281

AC XY:

204

AN XY:

726742

show subpopulations

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:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74372

show subpopulations

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.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leber congenital amaurosis 1

Pathogenic:4

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	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:3Other:1

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	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2020	- -
not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2023	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, 20050595, 22261762, 31816670, 32865313, 34008892, 35314386, 36369640, 37327959, 37510321, 34048777, 35836572, 36460718, 33109612) -

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

Jan 01, 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). 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: 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. -

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

Jul 28, 2021

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.50

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

4.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.5

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MVP

0.97

MPC

0.85

ClinPred

1.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over