ClinVar Miner

Submissions for variant NM_000532.5(PCCB):c.1304A>G (p.Tyr435Cys) (rs121964961)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000012798 SCV000790968 likely pathogenic Propionyl-CoA carboxylase deficiency 2017-04-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000012798 SCV000893635 pathogenic Propionyl-CoA carboxylase deficiency 2018-10-31 criteria provided, single submitter clinical testing
GeneReviews RCV000012798 SCV000055680 pathologic Propionyl-CoA carboxylase deficiency 2012-05-17 no assertion criteria provided curation Converted during submission to Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000012798 SCV000697269 pathogenic Propionyl-CoA carboxylase deficiency 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 likely pathogenic Propionyl-CoA carboxylase deficiency 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 435 of the PCCB protein (p.Tyr435Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs121964961, ExAC 0.05%). This variant has been reported variant has been reported to be homozygous or in combination with another PCCB variant in individuals with elevated propionylcarnitine (C3), findings that are highly specific for propionic acidemia (PMID: 12189489). ClinVar contains an entry for this variant (Variation ID: 12018). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000012798 SCV000033038 pathogenic Propionyl-CoA carboxylase deficiency 2002-08-01 no assertion criteria provided literature only
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000012798 SCV000267436 likely pathogenic Propionyl-CoA carboxylase deficiency 2016-03-18 criteria provided, single submitter reference population

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