ClinVar Miner

Submissions for variant NM_005506.4(SCARB2):c.1262C>T (p.Thr421Met) (rs149474488)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000713064 SCV000843631 uncertain significance not provided 2017-10-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000713064 SCV000332782 uncertain significance not provided 2015-06-30 criteria provided, single submitter clinical testing
GeneDx RCV000713064 SCV000242427 uncertain significance not provided 2018-09-25 criteria provided, single submitter clinical testing The T421M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T421M 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. The T421M 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 where amino acids with similar properties to Threonine 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 RCV000458265 SCV000545820 uncertain significance Progressive myoclonic epilepsy 2018-08-10 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 421 of the SCARB2 protein (p.Thr421Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs149474488, ExAC 0.08%) but has not been reported in the literature in individuals with a SCARB2-related disease. ClinVar contains an entry for this variant (Variation ID: 206716). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It is not expected to cause disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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