GeneBe

rs61749670

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP4_ModeratePVS1PP1PM2_SupportingPM3

This summary comes from the ClinGen Evidence Repository: The NM_000180.4(GUCY2D):c.389del (p.Pro130LeufsTer?) variant is a frameshift variant in exon 2 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.000002639, with 4 alleles / 1515578 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts), present at birth (1.0 pt), nystagmus (1.0 pt), extinguished ERG (0.5 pt), photophobia (1 pt) and dyschromatopsia (1 pt). That proband also had clinical exome sequencing performed without any additional potential causative variants identified (4 pts). Together these are highly specific for GUCY2D-related recessive retinopathy (total 9 points, PMID:37327959, PP4_Moderate). This variant has been reported in at least 4 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 8944027, 10951519). This variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygotes with variants not yet classified by the LCA/eoRD VCEP and who were not considered for this code. (1 total point, PM3). 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 homozygous state (PP1; PMID:8944027). 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, PP1, PM3, PP4_Moderate, PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 01/22/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226143/MONDO:0100453/167

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

GUCY2D
NM_000180.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:9O:1

Conservation

PhyloP100: 0.661

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 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.
PP1
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.389delC p.Pro130LeufsTer36 frameshift_variant Exon 2 of 20 ENST00000254854.5 NP_000171.1
GUCY2DXM_011523816.2 linkc.389delC p.Pro130LeufsTer36 frameshift_variant Exon 1 of 19 XP_011522118.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GUCY2DENST00000254854.5 linkc.389delC p.Pro130LeufsTer36 frameshift_variant Exon 2 of 20 1 NM_000180.4 ENSP00000254854.4

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151914
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000174
AC:
2
AN:
115224
AF XY:
0.0000157
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000433
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000233
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000220
AC:
3
AN:
1363664
Hom.:
0
Cov.:
34
AF XY:
0.00000149
AC XY:
1
AN XY:
672966
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
28620
American (AMR)
AF:
0.0000292
AC:
1
AN:
34296
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24332
East Asian (EAS)
AF:
0.00
AC:
0
AN:
33414
South Asian (SAS)
AF:
0.00
AC:
0
AN:
77790
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
33646
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4190
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1070648
Other (OTH)
AF:
0.0000353
AC:
2
AN:
56728
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
1
AN:
151914
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74204
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41370
American (AMR)
AF:
0.0000655
AC:
1
AN:
15260
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5176
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10562
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67928
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Leber congenital amaurosis 1 Pathogenic:4
Aug 01, 1998
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

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

Dec 24, 2024
3billion
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000098602 /PMID: 8944027). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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

Oct 28, 2021
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24265693, 8944027, 20683928, 20604683, 31814694, 32865313, 31736247, 32094338)

Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1 Pathogenic:1
Feb 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Pro130Leufs*36) in the GUCY2D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GUCY2D are known to be pathogenic (PMID: 10951519, 11328726). This variant is present in population databases (rs61749670, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Leber congenital amaurosis (PMID: 8944027, 20683928). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 98602). For these reasons, this variant has been classified as Pathogenic.

Leber congenital amaurosis Pathogenic:1
Jun 23, 2019
Sharon lab, Hadassah-Hebrew University Medical Center
Significance:Likely 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.389del (p.Pro130LeufsTer?) variant is a frameshift variant in exon 2 of 20, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.000002639, with 4 alleles / 1515578 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0004 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including a diagnosis of LCA (0.5 pts), present at birth (1.0 pt), nystagmus (1.0 pt), extinguished ERG (0.5 pt), photophobia (1 pt) and dyschromatopsia (1 pt). That proband also had clinical exome sequencing performed without any additional potential causative variants identified (4 pts). Together these are highly specific for GUCY2D-related recessive retinopathy (total 9 points, PMID: 37327959, PP4_Moderate). This variant has been reported in at least 4 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 8944027, 10951519). This variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygotes with variants not yet classified by the LCA/eoRD VCEP and who were not considered for this code. (1 total point, PM3). 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 homozygous state (PP1; PMID: 8944027). 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, PP1, PM3, PP4_Moderate, PM2_Supporting. (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
Mar 20, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
0.66
Mutation Taster
=4/196
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs61749670; hg19: chr17-7906751; API