17-8003050-G-A

Variant names:

• chr17-8003050-G-A
• rs281865409
• NM_000180.4:c.3G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP4 PM3 PM2_Supporting PVS1

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
• Clinical Significance: Pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 1.76

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]

ACMG classification

Verdict is Pathogenic. Variant got 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
GUCY2D	NM_000180.4	c.3G>A	p.Met1?	start_lost	Exon 2 of 20	ENST00000254854.5	NP_000171.1
GUCY2D	XM_011523816.2	c.3G>A	p.Met1?	start_lost	Exon 1 of 19		XP_011522118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5	c.3G>A	p.Met1?	start_lost	Exon 2 of 20	1	NM_000180.4	ENSP00000254854.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

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

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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
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
Varity_R		0.83
gMVP		0.61

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

LitVar

Other links and lift over

dbSNP: rs281865409; hg19: chr17-7906368;