rs552184470

Variant names:

• chr17-8003170-CCTGCTT-C
• rs552184470
• NM_000180.4:c.129_134delTCTGCT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS2 BS1

This summary comes from the ClinGen Evidence Repository: The NM_000180.4(GUCY2D):c.129_134del (p.Leu44_Leu45del) variant is the deletion of 2 amino acids from a repetitive region of the protein's leader sequence. This variant is present in gnomAD v4.1.0 at a GrpMax allele frequency of 0.005906, with 514 alleles / 80814 total alleles in the South Asian population, which is higher than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0016 (BS1). This variant has been found in the homozygous state in 21 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1, BS2. (VCEP specifications version 1.0.0; date of approval 01/22/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8365473/MONDO:0100453/167

• Frequency:
  • Genomes: 𝑓 0.0020 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (17 hom.)
• Consequence: GUCY2D NM_000180.4 disruptive_inframe_deletion
• Clinical Significance: Benign reviewed by expert panel P:3 U:9 B:5
• Conservation: PhyloP100: 4.32

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 Benign. Variant got -8 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.129_134delTCTGCT	p.Leu44_Leu45del	disruptive_inframe_deletion	Exon 2 of 20	ENST00000254854.5	NP_000171.1
GUCY2D	XM_011523816.2	c.129_134delTCTGCT	p.Leu44_Leu45del	disruptive_inframe_deletion	Exon 1 of 19		XP_011522118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY2D	ENST00000254854.5	c.129_134delTCTGCT	p.Leu44_Leu45del	disruptive_inframe_deletion	Exon 2 of 20	1	NM_000180.4	ENSP00000254854.4

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 152088 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00185 AC: 201 AN: 108698 Hom.: 1 AF XY: 0.00221 AC XY: 134 AN XY: 60574

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000751

Gnomad ASJ exome AF: 0.000141

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00504

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00203

Gnomad OTH exome AF: 0.00121

GnomAD4 exome AF: 0.00340 AC: 4629 AN: 1360336 Hom.: 17 AF XY: 0.00354 AC XY: 2374 AN XY: 670956

Gnomad4 AFR exome AF: 0.000428

Gnomad4 AMR exome AF: 0.00102

Gnomad4 ASJ exome AF: 0.000207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00630

Gnomad4 FIN exome AF: 0.000276

Gnomad4 NFE exome AF: 0.00365

Gnomad4 OTH exome AF: 0.00310

GnomAD4 genome AF: 0.00200 AC: 304 AN: 152196 Hom.: 4 Cov.: 32 AF XY: 0.00171 AC XY: 127 AN XY: 74406

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00319

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00183 Hom.: 1

Bravo AF: 0.00209

Asia WGS AF: 0.00174 AC: 6 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Pathogenic:3 Uncertain:9 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:4 Benign:1

Mar 28, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.129_134delTCTGCT variant in the GUCY2D gene has been reported previously in individuals with Leber congenital amaurosis or retinal dystrophy, but limited information was provided on the affected individuals (Stone et al., 2007; Sergouniotis et al., 2016). The c.129_134delTCTGCT variant causes an in-frame deletion of two Leucine residues starting at codon Leucine 44 amino acid, denoted p.Leu44_Leu45del. This amino acid deletion occurs at a position in a poly Leucine region that is not conserved. Reliable data is not available in large population cohorts to assess the frequency of the c.129_134delTCTGCT variant; however, it was observed in 176/63508 (0.277%) alleles from individuals undergoing testing at GeneDx (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.129_134delTCTGCT as a variant of uncertain significance. -

-

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 13, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cone-rod dystrophy 6 Uncertain:2

Oct 30, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:1

Jan 03, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GUCY2D c.129_134delTCTGCT (p.Leu44_Leu45del) results in an in-frame deletion that is predicted to remove two amino acids from the encoded protein. The variant allele was found at a frequency of 0.0018 in 108698 control chromosomes (including one homozygote), predominantly at a frequency of 0.005 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in GUCY2D causing Leber Congenital Amaurosis phenotype (0.0022). ClinVar contains an entry for this variant (Variation ID: 283615). Based on the evidence outlined above, the variant was classified as likely benign. -

Jan 01, 2019

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber congenital amaurosis 1 Pathogenic:1

Jan 30, 2021

Institute of Medical Molecular Genetics, University of Zurich

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Choroidal dystrophy, central areolar, 1 Pathogenic:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. This variant was inherited from a parent. -

Nystagmus;C0476397:Abnormal electroretinogram Pathogenic:1

Jul 11, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-rod dystrophy 6;C2931258:Leber congenital amaurosis 1;C4551884:Choroidal dystrophy, central areolar, 1;C5231408:Night blindness, congenital stationary, type1i Uncertain:1

Apr 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Uncertain:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GUCY2D-related disorder Benign:1

Nov 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GUCY2D-related recessive retinopathy Benign:1

Jan 30, 2025

ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000180.4(GUCY2D):c.129_134del (p.Leu44_Leu45del) variant is the deletion of 2 amino acids from a repetitive region of the protein's leader sequence. This variant is present in gnomAD v4.1.0 at a GrpMax allele frequency of 0.005906, with 514 alleles / 80814 total alleles in the South Asian population, which is higher than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0016 (BS1). This variant has been found in the homozygous state in 21 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). In summary, this variant meets the criteria to be classified as Benign for GUCY2D-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1, BS2. (VCEP specifications version 1.0.0; date of approval 01/22/2025). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs552184470; hg19: chr17-7906488;