rs61749755

Variant names:

• chr17-8009531-T-C
• rs61749755
• NM_000180.4:c.1694T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 11P and 1B. PS3_Supporting PP4 PM2_Supporting PM3_Strong BP2 PP1_Strong

This summary comes from the ClinGen Evidence Repository: NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) is a missense variant predicted to replace phenylalanine with serine at position p.565. This variant is present in gnomAD v4.1.0 at a total allele frequency of 6.197e-7, with 1 allele / 1613704 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 a homozygous proband with early-onset severe retinal dystrophy in cis with the NM_000180.4(GUCY2D):c.2633_2636del (p.Gln878ArgfsTer17) variant, which has been classified as pathogenic by the ClinGen LCA/eoRD VCEP (VCEP member-provided data, BP2). This variant has also been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 pt, PMID:8944027), and in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the variant confirmed in trans with the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant (1 pt, PMID:16505055), which has been classified as pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). Please note that one of these patients has been genotyped in a way that did not rule out the presence or absence of another GUCY2D variant in cis (PMID:16505055). This proband 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 3 similarly affected relatives in two different families, with the variant present in the homozygous state (PMID:8944027, PP1_Strong). The computational predictor REVEL gives a score of 0.494, which is below the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RETGC-1 protein function. The variant exhibited inability to be stimulated by GCAP1 (PMID:9888789), reduced RD3 binding by co-immunoprecipitation (PMID:25477517), and failure to localize to the plasma membrane along with RD3 and GCAP1 when exogenously expressed (PMID:25477517), indicating that it triggers a severe defect in protein function (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_Strong, PP4, and BP2. (VCEP specifications version 1.0.0; date of approval 01/22/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226054/MONDO:0100453/167

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GUCY2D NM_000180.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 O:1
• Conservation: PhyloP100: 4.70
• Publications: 16 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 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.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP2: 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.1694T>C	p.Phe565Ser	missense_variant	Exon 8 of 20	ENST00000254854.5	NP_000171.1
GUCY2D	XM_011523816.2	c.1694T>C	p.Phe565Ser	missense_variant	Exon 7 of 19		XP_011522118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5	c.1694T>C	p.Phe565Ser	missense_variant	Exon 8 of 20	1	NM_000180.4	ENSP00000254854.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251494 AF XY: 0.00

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: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461532 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727096

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111684

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leber congenital amaurosis 1 Pathogenic:2

Jan 12, 1999

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

- -

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

NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) is a missense variant predicted to replace phenylalanine with serine at position p.565. This variant is present in gnomAD v4.1.0 at a total allele frequency of 6.197e-7, with 1 allele / 1613704 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 a homozygous proband with early-onset severe retinal dystrophy in cis with the NM_000180.4(GUCY2D):c.2633_2636del (p.Gln878ArgfsTer17) variant, which has been classified as pathogenic by the ClinGen LCA/eoRD VCEP (VCEP member-provided data, BP2). This variant has also been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 pt, PMID: 8944027), and in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the variant confirmed in trans with the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant (1 pt, PMID: 16505055), which has been classified as pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). Please note that one of these patients has been genotyped in a way that did not rule out the presence or absence of another GUCY2D variant in cis (PMID: 16505055). This proband 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 3 similarly affected relatives in two different families, with the variant present in the homozygous state (PMID: 8944027, PP1_Strong). The computational predictor REVEL gives a score of 0.494, which is below the ClinGen LCA/eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RETGC-1 protein function. The variant exhibited inability to be stimulated by GCAP1 (PMID: 9888789), reduced RD3 binding by co-immunoprecipitation (PMID: 25477517), and failure to localize to the plasma membrane along with RD3 and GCAP1 when exogenously expressed (PMID: 25477517), indicating that it triggers a severe defect in protein function (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_Strong, PP4, and BP2. (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
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.087	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.94		Loss of stability (P = 0.0077);
MVP		0.89
MPC		1.1
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.43
gMVP		0.87
Mutation Taster		=31/69	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs61749755; hg19: chr17-7912849;