ClinVar Miner

Submissions for variant NM_000180.4(GUCY2D):c.935C>T (p.Thr312Met)

gnomAD frequency: 0.00003  dbSNP: rs61749673
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000084906 SCV001986109 uncertain significance not provided 2024-11-13 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15691574, 26047050, 20079931, 21602930, 26253563, 27375279, 27422788, 34048777, 17964524, 19959640, 31964843, 16205573, 29061346)
3billion RCV001250818 SCV002572926 likely pathogenic Leber congenital amaurosis 1 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.60). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GUCY2D-related disorder (ClinVar ID: VCV000098610 / PMID: 15691574 , 26047050 / 3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset). Different missense changes at the same codon (p.Thr312Arg, p.Thr312Pro) have been reported to be associated with GUCY2D-related disorder (PMID: 17964524 , 26047050). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp RCV003764783 SCV004593105 likely pathogenic Cone-rod dystrophy 6; Leber congenital amaurosis 1 2023-12-12 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 312 of the GUCY2D protein (p.Thr312Met). This variant is present in population databases (rs61749673, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive GUCY2D-related conditions (PMID: 15691574, 16205573, 19959640, 31964843, 34048777). ClinVar contains an entry for this variant (Variation ID: 98610). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GUCY2D protein function. This variant disrupts the p.Thr312 amino acid residue in GUCY2D. Other variant(s) that disrupt this residue have been observed in individuals with GUCY2D-related conditions (PMID: 26047050), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Retina International RCV000084906 SCV000117042 not provided not provided no assertion provided not provided
Laboratory of Genetics in Ophthalmology, Institut Imagine RCV001250818 SCV001426303 likely pathogenic Leber congenital amaurosis 1 no assertion criteria provided research

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