Submissions for variant NM_000180.4(GUCY2D):c.1979G>A (p.Arg660Gln)

gnomAD frequency: 0.00013  dbSNP: rs61750162

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001047346	SCV001211298	uncertain significance	Cone-rod dystrophy 6; Leber congenital amaurosis 1	2022-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 660 of the GUCY2D protein (p.Arg660Gln). This variant is present in population databases (rs61750162, gnomAD 0.07%). This missense change has been observed in individual(s) with Leber congenital amaurosis (PMID: 10766140, 20079931). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 98555). 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. This variant disrupts the p.Arg660 amino acid residue in GUCY2D. Other variant(s) that disrupt this residue have been observed in individuals with GUCY2D-related conditions (PMID: 21602930), which suggests that this may be a clinically significant amino acid residue. 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.
GeneDx	RCV000084848	SCV001785453	uncertain significance	not provided	2021-11-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in the heterozygous state in an individual with Leber congenital amaurosis in published literature, however familial segregation information was not reported (Lotery et al., 2000); Observed with an additional GUCY2D variant in patients with Leber congenital amaurosis in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Walia et al., 2010; Xu et al., 2016); This variant is associated with the following publications: (PMID: 34048777, 10766140, 21602930, 29061346, 20079931, 27375279)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387757	SCV004099540	uncertain significance	not specified	2023-09-06	criteria provided, single submitter	clinical testing	Variant summary: GUCY2D c.1979G>A (p.Arg660Gln) results in a conservative amino acid change located in the serine-threonine/tyrosine-protein kinase, catalytic domain (IPR001245) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 251346 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GUCY2D causing Leber Congenital Amaurosis (0.00038 vs 0.0022), allowing no conclusion about variant significance. c.1979G>A has been reported in the literature in the heterozygous state in individuals affected with Leber Congenital Amaurosis, including in a pair of affected siblings where an unspecified deletion was suspected to be inherited in trans, however it was located outside of the coding region of the GUCY2D gene (e.g. Lotery_2000, Milam_2003, Walia_2010). These reports do not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. 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: 10766140, 12623820, 20079931). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Retina International	RCV000084848	SCV000116984	not provided	not provided		no assertion provided	not provided