Submissions for variant NM_000180.4(GUCY2D):c.129_134del (p.Leu44_Leu45del)

dbSNP: rs552184470

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen	RCV005053941	SCV005687728	benign	GUCY2D-related recessive retinopathy	2025-01-30	reviewed by expert panel	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).
Eurofins Ntd Llc (ga)	RCV000415795	SCV000335816	uncertain significance	not provided	2015-10-13	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414862	SCV000492721	likely pathogenic	Nystagmus; Abnormal electroretinogram	2014-07-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000415795	SCV000493155	likely benign	not provided	2018-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000415795	SCV000577499	uncertain significance	not provided	2017-03-28	criteria provided, single submitter	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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000784899	SCV000923438	uncertain significance	not specified	2019-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081143	SCV001020636	likely benign	Cone-rod dystrophy 6; Leber congenital amaurosis 1	2025-02-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000989733	SCV001140277	uncertain significance	Cone-rod dystrophy 6	2019-05-28	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199370	SCV001370469	likely pathogenic	Choroidal dystrophy, central areolar, 1	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. This variant was inherited from a parent.
Institute of Medical Molecular Genetics, University of Zurich	RCV001352942	SCV001548008	likely pathogenic	Leber congenital amaurosis 1	2021-01-30	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816490	SCV005072966	uncertain significance	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005016671	SCV005652762	uncertain significance	Choroidal dystrophy, central areolar, 1; Cone-rod dystrophy 6; Leber congenital amaurosis 1; Night blindness, congenital stationary, type1i	2024-04-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000784899	SCV005888409	likely benign	not specified	2025-01-03	criteria provided, single submitter	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.
Clinical Genetics, Academic Medical Center	RCV000415795	SCV001920051	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000415795	SCV001969006	uncertain significance	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000989733	SCV004099313	uncertain significance	Cone-rod dystrophy 6	2023-10-30	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003939980	SCV004750478	likely benign	GUCY2D-related disorder	2019-11-01	no assertion criteria provided	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).