17-8003050-G-A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PP4PM2_SupportingPM3

This summary comes from the ClinGen Evidence Repository: The NM_000180.4(GUCY2D):c.3G>A variant is predicted to change the initiation codon (p.Met1) to a stop codon, with no known alternative start codons present (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_supporting). This variant has been reported in 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (0.5 points each), PMIDs: 37327959, 10951519). (1 total point, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5 pts), severe visual loss present at birth (1 pt), congenital nystagmus (1 pt), photophobia (1 pt), dyschromatopsia (1 pt), and nonrecordable ERG (0.5 pts) which together are specific for GUCY2D-related recessive retinopathy (total of 5 points, PMID:37327959, PP4). 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: PVS1, PM2_supporting, PP4, PM3. (VCEP specifications version 1.0.0; date of approval 01/22/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226144/MONDO:0100453/167

Frequency

Genomes: not found (cov: 33)

Consequence

GUCY2D
NM_000180.4 start_lost

Scores

6
3
7

Clinical Significance

Pathogenic reviewed by expert panel P:2O:1

Conservation

PhyloP100: 1.76

Publications

2 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

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1
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.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GUCY2DNM_000180.4 linkc.3G>A p.Met1? start_lost Exon 2 of 20 ENST00000254854.5 NP_000171.1 Q02846
GUCY2DXM_011523816.2 linkc.3G>A p.Met1? start_lost Exon 1 of 19 XP_011522118.1 Q02846

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GUCY2DENST00000254854.5 linkc.3G>A p.Met1? start_lost Exon 2 of 20 1 NM_000180.4 ENSP00000254854.4 Q02846

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Leber congenital amaurosis 1 Pathogenic:1
-
Laboratory of Genetics in Ophthalmology, Institut Imagine
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:research

- -

GUCY2D-related recessive retinopathy Pathogenic:1
Jan 30, 2025
ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen
Significance:Pathogenic
Review Status:reviewed by expert panel
Collection Method:curation

The NM_000180.4(GUCY2D):c.3G>A variant is predicted to change the initiation codon (p.Met1) to a stop codon, with no known alternative start codons present (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_supporting). This variant has been reported in 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (0.5 points each), PMIDs: 37327959, 10951519). (1 total point, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5 pts), severe visual loss present at birth (1 pt), congenital nystagmus (1 pt), photophobia (1 pt), dyschromatopsia (1 pt), and nonrecordable ERG (0.5 pts) which together are specific for GUCY2D-related recessive retinopathy (total of 5 points, PMID: 37327959, PP4). 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: PVS1, PM2_supporting, PP4, PM3. (VCEP specifications version 1.0.0; date of approval 01/22/2025). -

not provided Other:1
-
Retina International
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.14
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.097
T
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.21
FATHMM_MKL
Benign
0.59
D
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
1.0
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Benign
-0.59
T
PhyloP100
1.8
PROVEAN
Benign
-0.63
N
REVEL
Uncertain
0.45
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.0010
B
Vest4
0.94
MutPred
1.0
Loss of helix (P = 0.1299);
MVP
0.86
ClinPred
0.99
D
GERP RS
1.6
PromoterAI
-0.010
Neutral
Varity_R
0.83
gMVP
0.61
Mutation Taster
=6/194
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs281865409; hg19: chr17-7906368; API