ClinVar Miner

Submissions for variant NM_000532.5(PCCB):c.1316A>G (p.Tyr439Cys) (rs769521436)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490483 SCV000267437 likely pathogenic Propionic acidemia 2016-03-18 criteria provided, single submitter reference population
Counsyl RCV000490483 SCV000792715 likely pathogenic Propionic acidemia 2017-07-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000490483 SCV000919959 pathogenic Propionic acidemia 2018-06-07 criteria provided, single submitter clinical testing Variant summary: PCCB c.1316A>G (p.Tyr439Cys) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, C-terminal domain (IPR011763) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 246228 control chromosomes, mostly occuring in the East Asian subpopulation. c.1316A>G has been reported in the literature in individuals affected with Propionic Acidemia; all of these cases were found in East Asian populations (Kim 2002, Yorifuji 2002, Chiu 2014). These data indicate that the variant is likely to be associated with disease. These publications also reported a significantly decreased enzyme activity in the affected individuals, with the most pronounced variant effect resulting in <10% of normal activity. A recent population study demonstrated a founder effect for the variant in the Korean population based on haplotype analysis (Park 2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000490483 SCV001580904 pathogenic Propionic acidemia 2020-10-07 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 439 of the PCCB protein (p.Tyr439Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs769521436, ExAC 0.02%). This variant has been observed in individual(s) with PCCB-related conditions (PMID: 12189489, 12409268, 31808324). ClinVar contains an entry for this variant (Variation ID: 225429). 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. For these reasons, this variant has been classified as Pathogenic.

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