ClinVar Miner

Submissions for variant NM_000282.4(PCCA):c.229C>T (p.Arg77Trp) (rs141371306)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665579 SCV000789725 likely pathogenic Propionic acidemia 2017-02-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000665579 SCV000919957 pathogenic Propionic acidemia 2018-11-29 criteria provided, single submitter clinical testing Variant summary: PCCA c.229C>T (p.Arg77Trp) results in a non-conservative amino acid change located in the Biotin carboxylation domain & Biotin carboxylase-like, N-terminal domain 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 245438 control chromosomes (gnomAD). c.229C>T has been reported in the literature in individuals affected with Propionic Acidemia (Chiu_2014, Perez_2010, Yang_2004, Perez-Cerda_2000). These data indicate that the variant is likely to be associated with disease. Experimental evidence reported in a publication evaluating an impact on protein function (Clavero_2002) demonstrated the variant to clearly diminish PCC activity (<10% of normal activity). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000665579 SCV001580695 pathogenic Propionic acidemia 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 77 of the PCCA protein (p.Arg77Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs141371306, ExAC 0.03%). This variant has been observed in individual(s) with propionic acidemia (PMID: 10780784, 15059621, 20549364, 24863100). This variant is also known as 154C>T (R52W) in the literature. ClinVar contains an entry for this variant (Variation ID: 550747). This variant has been reported to affect PCCA protein function (PMID: 12385775). For these reasons, this variant has been classified as Pathogenic.

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