ClinVar Miner

Submissions for variant NM_012414.4(RAB3GAP2):c.3171G>A (p.Met1057Ile) (rs368434757)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497690 SCV000590608 uncertain significance not provided 2017-06-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RAB3GAP2 gene. The M1057I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The M1057I variant is observed in 4/11,566 (0.03%) alleles from individuals of Latino background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M1057I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Methionine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000638448 SCV000759971 uncertain significance Cataract-intellectual disability-hypogonadism syndrome; Warburg micro syndrome 2 2018-07-02 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 1057 of the RAB3GAP2 protein (p.Met1057Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs368434757, ExAC 0.03%). This variant has not been reported in the literature in individuals with RAB3GAP2-related disease. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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