chr17-8014701-G-A

Position:

• chr17-8014701-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000180.4(GUCY2D):​c.2513G>A​(p.Arg838His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R838G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GUCY2D NM_000180.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19 U:1 O:1
• Conservation: PhyloP100: 10.0

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]

ENSG00000279174 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.921
• PP5: Variant 17-8014701-G-A is Pathogenic according to our data. Variant chr17-8014701-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8014701-G-A is described in Lovd as [Pathogenic]. Variant chr17-8014701-G-A is described in Lovd as [Pathogenic]. Variant chr17-8014701-G-A is described in Lovd as [Likely_pathogenic]. Variant chr17-8014701-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.2513G>A	p.Arg838His	missense_variant	13/20	ENST00000254854.5	NP_000171.1
GUCY2D	XM_011523816.2	c.2513G>A	p.Arg838His	missense_variant	12/19		XP_011522118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5	c.2513G>A	p.Arg838His	missense_variant	13/20	1	NM_000180.4	ENSP00000254854.4
ENSG00000279174	ENST00000623126.1	n.1678C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456862 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 724742

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cone-rod dystrophy 6 Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Sep 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 07, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2003	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

not provided Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2018	- -
not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2022	Not observed in large population cohorts (gnomAD); Published functional studies suggest a damaging effect (dominant negative effect with a higher activity compared to wild type) (Wilkie et al., 2000); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28041643, 25082885, 23563732, 18487367, 22183351, 22968130, 24480840, 11115851, 25283059, 24875811, 15175914, 26298565, 29061346, 28181551, 25515582, 10676808, 11565546, 22194653, 29555955, 31456290, 32821499, 32036094, 32581362, 34048777, 32811265, 12552567, 33691693) -

Retinal dystrophy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 14, 2018	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2022	- -

Macular dystrophy;C3665347:Visual impairment Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MNM Diagnostics

Jul 31, 2019

According to ACMG Guidelines, the variant meets the following evidence of pathogenicity: PS1, PS2, PS3, PP1, PM2, PP5. -

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 arginine, which is basic and polar, with histidine, which is basic and polar, at codon 838 of the GUCY2D protein (p.Arg838His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant cone-rod dystrophy (PMID: 12552567, 26298565). It has also been observed to segregate with disease in related individuals. This variant is also known as 2586G>A. ClinVar contains an entry for this variant (Variation ID: 9357). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GUCY2D protein function. Experimental studies have shown that this missense change affects GUCY2D function (PMID: 11115851). This variant disrupts the p.Arg838 amino acid residue in GUCY2D. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11115851, 12552567, 24875811, 26298565). 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-rod dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Jul 24, 2023

Clinical significance based on ACMG v2.0 -

Cone dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Retinitis pigmentosa Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Apr 01, 2021

The p.Arg838His variant in GUCY2D was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PS3, PM1, PP1. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Progressive cone dystrophy (without rod involvement) Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.62		Loss of solvent accessibility (P = 0.0635);
MVP		0.98
MPC		1.9
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.93

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: rs61750173; hg19: chr17-7918019; COSMIC: COSV54695753; COSMIC: COSV54695753;