ClinVar Miner

Submissions for variant NM_018849.3(ABCB4):c.2144C>T (p.Thr715Ile) (rs138773456)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724634 SCV000700790 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000724634 SCV000521298 uncertain significance not provided 2018-07-05 criteria provided, single submitter clinical testing The T715I variant in the ABCB4 gene has been reported previously in progressive familialintrahepatic cholestasis type 3, in an affected individual who was heterozyous for the T715I variantand no second variant was identified (Degiorgio et al., 2007). Degiorgio et al. (2007) concluded thatthe effect of the T715I variant on the ABCB4 gene is not clear and further characterization of thisvariant is required. Although not present in the homozygous state, the NHLBI Exome SequencingProject reports T715I was observed in 10/8600 (0.12%) alleles from individuals of EuropeanAmerican background, indicating it may be a rare variant in this population. The T715I variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure asthese residues differ in polarity, charge, size and/or other properties. This substitution occurs at aposition that is not conserved. In silico analysis is inconsistent in its predictions as to whether or notthe variant is damaging to the protein structure/function. A missense variant in a nearby residue(F711S) has been reported in the Human Gene Mutation Database in association with progressivefamilial intrahepatic cholestasis (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. We interpret T715I as a variant of uncertain significance.

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