ClinVar Miner

Submissions for variant NM_000532.5(PCCB):c.1304A>G (p.Tyr435Cys)

gnomAD frequency: 0.00002  dbSNP: rs121964961
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000012798 SCV000267436 likely pathogenic Propionic acidemia 2016-03-18 criteria provided, single submitter reference population
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000012798 SCV000697269 pathogenic Propionic acidemia 2017-03-20 criteria provided, single submitter clinical testing Variant summary: The PCCB c.1304A>G (p.Tyr435Cys) variant located in the CoA carboxyltransferase C-terminal domain (via InterPro) involves the alteration of a conserved nucleotide and is predicted to be damaging by 5/5 in silico tools. This variant was found in 8/121510 control chromosomes including broad and large populations from ExAC at a heterozygous allele frequency of 0.0000658, which does not exceed the estimated maximal expected allele frequency of a pathogenic PCCB variant (0.0025). This variant is known to be a common pathogenic variant that causes mild propionic academia in Japanese population (Yorifuji_2002). The carrier frequency of this variant in Japanese population was estimated to be 1/86.5 by the authors. Enzymatic activity in peripheral blood leukocytes of patients carrying this variant in homozygous state or compound heterozygous state revealed significantly reduced but residual activity consistent with the phenotype caused (Yorifuji_2002). It was not found in a cohort of 30 patients with more severe form of disease in the same population (Yang_2004). Multiple reputable databases and the publications have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae RCV000012798 SCV000836588 pathogenic Propionic acidemia 2021-12-02 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 435 of the PCCB protein (p.Tyr435Cys). This variant is present in population databases (rs121964961, gnomAD 0.06%). This missense change has been observed in individuals with propionic acidemia (PMID: 12189489). ClinVar contains an entry for this variant (Variation ID: 12018). 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.
Fulgent Genetics,Fulgent Genetics RCV000012798 SCV000893635 pathogenic Propionic acidemia 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV000012798 SCV001162961 pathogenic Propionic acidemia criteria provided, single submitter clinical testing
OMIM RCV000012798 SCV000033038 pathogenic Propionic acidemia 2002-08-01 no assertion criteria provided literature only
GeneReviews RCV000012798 SCV000055680 pathologic Propionic acidemia 2012-05-17 no assertion criteria provided curation Converted during submission to Pathogenic.
Counsyl RCV000012798 SCV000790968 likely pathogenic Propionic acidemia 2017-04-17 no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000012798 SCV002021619 likely pathogenic Propionic acidemia 2021-10-29 no assertion criteria provided clinical testing

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