ClinVar Miner

Submissions for variant NM_000532.5(PCCB):c.1146T>A (p.Asp382Glu)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001384626 SCV001584197 pathogenic Propionic acidemia 2020-08-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 382 of the PCCB protein (p.Asp382Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with propionic acidemia (PMID: 30274917). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PCCB protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this variant affects PCCB protein function (PMID: 30274917). For these reasons, this variant has been classified as Pathogenic.

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