rs61749668

Positions:

• chr17-8003354-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5 PP3 PP5_Very_Strong

The NM_000180.4(GUCY2D):​c.307G>A​(p.Glu103Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000175 in 1,469,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. E103V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: GUCY2D NM_000180.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 6.79

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 11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756
• PP5: Variant 17-8003354-G-A is Pathogenic according to our data. Variant chr17-8003354-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 98590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8003354-G-A is described in Lovd as [Pathogenic]. Variant chr17-8003354-G-A is described in Lovd as [Likely_pathogenic]. Variant chr17-8003354-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCY2D	NM_000180.4	c.307G>A	p.Glu103Lys	missense_variant	2/20	ENST00000254854.5	NP_000171.1
GUCY2D	XM_011523816.2	c.307G>A	p.Glu103Lys	missense_variant	1/19		XP_011522118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5	c.307G>A	p.Glu103Lys	missense_variant	2/20	1	NM_000180.4	ENSP00000254854.4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000589

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000191 AC: 252 AN: 1317544 Hom.: 0 Cov.: 34 AF XY: 0.000198 AC XY: 129 AN XY: 649942

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000238

Gnomad4 OTH exome AF: 0.0000367

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152004 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74264

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber congenital amaurosis 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function variants are associated with Leber congenital amaurosis 1 (LCA, MIM#204000) and gain of function variants are associated with Cone-rod dystrophy 6 (MIM#601777). Gain of function variants tend to cluster in the linker domain specifically around p.838 (OMIM, PMIDs: 29061346, 11709018, 11115851). (I) 0108 - This gene is associated with both recessive and dominant disease. Heterozygotes with autosomal dominant disease tend to be less severely affected (OMIM, PMID: 29061346). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v3 <0.01 for a recessive condition (5 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated receptor family ligand binding region (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in over ten individuals with Leber congenital amaurosis (ClinVar, PMIDs: 31704230, 18055820, 28041643, 29178642). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 30, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

not provided Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17964524, 34048777, 32581362, 18055820, 31704230, 28041643, 29178642) -
not provided, no classification provided	literature only	Retina International	-	- -

Leber congenital amaurosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 16, 2024

Variant summary: GUCY2D c.307G>A (p.Glu103Lys) results in a conservative amino acid change located in the Receptor, ligand binding region (IPR001828) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.307G>A has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis (example, Bouzia_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Additionally, at least one variant at the Glu103 residue has been reported as associated with disease in ClinVar (p.Glu103Val), suggesting that this codon is functionally important. These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 31704230). ClinVar contains an entry for this variant (Variation ID: 98590). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 103 of the GUCY2D protein (p.Glu103Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive GUCY2D-related conditions (PMID: 28041643, 29178642; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 98590). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GUCY2D protein function with a negative predictive value of 80%. This variant disrupts the p.Glu103 amino acid residue in GUCY2D. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21602930, 34048777). 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

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.068	D
MutationAssessor	Uncertain	2.2	M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.55
Sift	Benign	0.049	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.35
MutPred		0.59		Gain of methylation at E103 (P = 0.0191);
MVP		0.94
MPC		2.6
ClinPred		0.84	D
GERP RS		4.0
Varity_R		0.30
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs61749668; hg19: chr17-7906672;