17-8014700-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM5PP2PP3_ModeratePP5_Very_Strong

The NM_000180.4(GUCY2D):c.2512C>T(p.Arg838Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R838P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GUCY2D
NM_000180.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17O:1

Conservation

PhyloP100: 0.696

Publications

61 publications found

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 Gene-Disease associations (from GenCC):

cone-rod dystrophy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
GUCY2D-related dominant retinopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
GUCY2D-related recessive retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Leber congenital amaurosis 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
cone-rod dystrophy 6
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
night blindness, congenital stationary, type1i
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
central areolar choroidal dystrophy
Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet

GUCY2D links:

ENSG00000279174 (HGNC:):

ENSG00000279174 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000180.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-8014701-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 811743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 55 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 0.78087 (below the threshold of 3.09). Trascript score misZ: 0.0082692 (below the threshold of 3.09). GenCC associations: The gene is linked to Leber congenital amaurosis 1, GUCY2D-related dominant retinopathy, central areolar choroidal dystrophy, cone-rod dystrophy, cone-rod dystrophy 6, night blindness, congenital stationary, type1i, GUCY2D-related recessive retinopathy, Leber congenital amaurosis.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.93

PP5

Variant 17-8014700-C-T is Pathogenic according to our data. Variant chr17-8014700-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 9355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY2D	NM_000180.4 link	c.2512C>T	p.Arg838Cys	missense_variant	Exon 13 of 20	ENST00000254854.5	NP_000171.1
GUCY2D	XM_011523816.2 link	c.2512C>T	p.Arg838Cys	missense_variant	Exon 12 of 19		XP_011522118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GUCY2D	ENST00000254854.5 link	c.2512C>T	p.Arg838Cys	missense_variant	Exon 13 of 20	1	NM_000180.4	ENSP00000254854.4
ENSG00000279174	ENST00000623126.1 link	n.1679G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
ENSG00000299408	ENST00000763246.1 link	n.164G>A		non_coding_transcript_exon_variant	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151928

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251422

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111962

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151928

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74186

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41342

American (AMR)

AF:

0.00

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cone-rod dystrophy 6

Pathogenic:9

Sep 23, 2024

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Suma Genomics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 22, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Sep 01, 2016

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Department of Ophthalmology and Visual Sciences Kyoto University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Genomics England Pilot Project, Genomics England

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 05, 2025

SingHealth Duke-NUS Institute of Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 11115851, PS3). REVEL score is 0.779 (PP3_mod). Other missense variants on this amino acid residue are classified as pathogenic (PM5). gnomAD genomes homozygous allele count is less than 2 for AD/AR gene GUCY2D (PM2). Located in a mutational hotspot where >50% of variants are pathogenic (PM1). Internal data shows cosegregation with disease (PP1) -

Feb 22, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

_x000D_ Criteria applied: PS4, PM5_STR, PM1_SUP, PM2_SUP, PP3 -

not provided

Pathogenic:2Other:1

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GUCY2D: PM2, PM5, PP1:Moderate, PS4:Moderate, PP3, PS3:Supporting -

Apr 04, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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) -

Retinal dystrophy

Pathogenic:2

Jun 18, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2020

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leber congenital amaurosis 1

Pathogenic:1

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Choroidal dystrophy, central areolar, 1

Pathogenic:1

Apr 30, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. -

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

Pathogenic:1

Oct 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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). 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: 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. -

Cone dystrophy

Pathogenic:1

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.9

PhyloP100

0.70

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-7.6

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MutPred

0.67

Loss of solvent accessibility (P = 0.0146);

MVP

0.97

MPC

2.0

ClinPred

1.0

GERP RS

5.0

Varity_R

0.93

gMVP

0.96

Mutation Taster

=18/82

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over