ClinVar Miner

Submissions for variant NM_005506.4(SCARB2):c.194A>G (p.Tyr65Cys) (rs138955932)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188794 SCV000242418 uncertain significance not provided 2018-05-18 criteria provided, single submitter clinical testing p.Tyr65Cys (TAT>TGT): c.194 A>G in exon 2 of the SCARB2 gene (NM_005506.3) A variant of unknown significance has been identified in the SCARB2 gene. The Y65C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The Y65C variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the Y65C variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, missense mutations in nearby residues have not been reported in association with SCARB2-related disorders. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000691814 SCV000819607 uncertain significance Progressive myoclonic epilepsy 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 65 of the SCARB2 protein (p.Tyr65Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs138955932, ExAC 0.2%). This variant has not been reported in the literature in individuals with SCARB2-related disease. ClinVar contains an entry for this variant (Variation ID: 206708). 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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