ClinVar Miner

Submissions for variant NM_000180.4(GUCY2D):c.2620G>A (p.Glu874Lys)

gnomAD frequency: 0.00001  dbSNP: rs1001538483
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481166 SCV000573136 uncertain significance not provided 2022-04-23 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with retinal dystrophy in published literature and referred for genetic testing at GeneDx who also harbored a second GUCY2D variant, although segregation information was not provided for all cases (Liu et al., 2020; Hahn et al., 2022); This variant is associated with the following publications: (PMID: 35314386, 32821499)
Labcorp Genetics (formerly Invitae), Labcorp RCV001047394 SCV001211350 uncertain significance Cone-rod dystrophy 6; Leber congenital amaurosis 1 2022-10-15 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 874 of the GUCY2D protein (p.Glu874Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GUCY2D-related conditions (PMID: 32821499). ClinVar contains an entry for this variant (Variation ID: 423435). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
Mendelics RCV002248709 SCV002517163 uncertain significance not specified 2022-05-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002248709 SCV005185117 uncertain significance not specified 2024-05-31 criteria provided, single submitter clinical testing Variant summary: GUCY2D c.2620G>A (p.Glu874Lys) results in a conservative amino acid change located in the Adenylyl cyclase class-3/4/guanylyl cyclase domain (IPR001054) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251468 control chromosomes. c.2620G>A has been reported in the literature in compound heterozygous individuals affected with Leber Congenital Amaurosis (Liu_2020, Maltese_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32821499, 35836572, 36284460). ClinVar contains an entry for this variant (Variation ID: 423435). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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