ClinVar Miner

Submissions for variant NM_000180.4(GUCY2D):c.121C>T (p.Leu41Phe)

gnomAD frequency: 0.00010  dbSNP: rs61749664
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000084829 SCV000610019 uncertain significance not provided 2017-04-26 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000084829 SCV000883964 uncertain significance not provided 2018-06-22 criteria provided, single submitter clinical testing The GUCY2D c.121C>T;p.Leu41Phe variant (rs61749664) has been published in the literature in at least one individual with Leber congenital amaurosis (Perrault 2000). The variant is reported in the ClinVar database (Variation ID: 98538 ) and in the Genome Aggregation Database with an overall allele frequency of 0.01% (15/135906 alleles). The leucine at codon 41 is moderately conserved across species and computational programs (PolyPhen2, SIFT) predict this variant is tolerated. However, at least one publication indicates that this protein shows reduced function (Zulliger 2015). Considering available information, the clinical significance of this variant cannot be determined with certainty. Pathogenic GUCY2D variants are causative for autosomal dominant cone-rod dystrophy or autosomal recessive Leber congenital amaurosis (OMIM#600179). References: Perrault I et al. Spectrum of retGC1 mutations in Leber's congenital amaurosis. Eur J Hum Genet. 2000 8(8):578-82. Zulliger R et al. Impaired association of retinal degeneration-3 with guanylate cyclase-1 and guanylate cyclase-activating protein-1 leads to leber congenital amaurosis-1. J Biol Chem. 2015 290(6):3488-99.
Invitae RCV001227542 SCV001399903 uncertain significance Cone-rod dystrophy 6; Leber congenital amaurosis 1 2022-10-30 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 41 of the GUCY2D protein (p.Leu41Phe). This variant is present in population databases (rs61749664, gnomAD 0.03%). This missense change has been observed in individual(s) with Leber congenital amaurosis or autosomal recessive retinitis pigmentosa (PMID: 10951519, 15024725, 18055816, 22695961). ClinVar contains an entry for this variant (Variation ID: 98538). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GUCY2D function (PMID: 11328726, 25477517). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen RCV000084829 SCV001746270 uncertain significance not provided 2021-10-01 criteria provided, single submitter clinical testing
GeneDx RCV000084829 SCV001772814 uncertain significance not provided 2020-02-13 criteria provided, single submitter clinical testing Reported previously in the heterozygous state in two siblings with Leber congenital amaurosis and in one family with autosomal recessive retinitis pigmentosa; none of these individuals harbored a second identifiable GUCY2D variant (Perrault et al., 2000; Vallespin et al., 2007); Published functional studies are inconclusive, with both reduced binding to RD3 protein as well as normal basal activity reported (Zulliger et al., 2015; Sharon et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31626798, 29061346, 20012162, 18055816, 10951519, 19941040, 22695961, 25477517, 31574917)
Genetics and Molecular Pathology, SA Pathology RCV002466425 SCV002761882 uncertain significance Cone-rod dystrophy 6 2022-02-01 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002477248 SCV002776397 uncertain significance Choroidal dystrophy, central areolar, 1; Cone-rod dystrophy 6; Leber congenital amaurosis 1; Night blindness, congenital stationary, type1i 2021-10-28 criteria provided, single submitter clinical testing
Retina International RCV000084829 SCV000116965 not provided not provided no assertion provided not provided

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