ClinVar Miner

Submissions for variant NM_021911.2(GABRB2):c.902A>G (p.Tyr301Cys) (rs1064794996)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479025 SCV000570370 likely pathogenic not provided 2016-06-02 criteria provided, single submitter clinical testing The Y301C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y301C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (V302M/N, A304V) have been reported in the Human Gene Mutation Database in association with GABRB2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000688521 SCV000816137 uncertain significance Intellectual disability 2018-05-07 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 301 of the GABRB2 protein (p.Tyr301Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GABRB2-related disease. ClinVar contains an entry for this variant (Variation ID: 421234). 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, 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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