ClinVar Miner

Submissions for variant NM_000532.5(PCCB):c.1218_1231delinsTAGAGCACAGGA (p.Gly407fs) (rs397507445)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000370248 SCV000225528 pathogenic not provided 2017-12-14 criteria provided, single submitter clinical testing
GeneDx RCV000370248 SCV000329828 pathogenic not provided 2017-05-23 criteria provided, single submitter clinical testing The c.1218_1231del14ins12 variant in the PCCB gene has been reported previously in association with propionic acidemia (Gravel et al., 1994; Alberola et al., 2011). The c.1218_1231del14ins12 variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server) This variant causes a frameshift starting with codon Glycine 407, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Gly407ArgfsX14. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret c.1218_1231del14ins12 to be a pathogenic variant.
GeneReviews RCV000032124 SCV000055677 pathologic Propionyl-CoA carboxylase deficiency 2012-05-17 no assertion criteria provided curation Converted during submission to Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000032124 SCV000697267 pathogenic Propionyl-CoA carboxylase deficiency 2016-01-21 criteria provided, single submitter clinical testing Variant summary: This c.1218_1231delinsTAGAGCACAGGA (or c.1218_1231del14ins12) variant causes a frameshift, which alters the proteins amino acid sequence beginning at position 407 and leads to a premature termination codon 14 amino acids downstream. It is predicted to cause a truncated or absent PCCB protein. Loss-of-function due to mutations in this gene is an established disease mechanism in Propionic Acidemia. This variant was not found in approximately 121298 controls chromosomes (including broad and large populations of ExAC). In literature and databases, this variant has been reported or found as the most common pathogenic variant in Caucasians that causes Propionic Acidemia. One clinical lab and multiple databases have classified this variant as pathogenic. Taken together, this variant has been classified as a Pathogenic.
Invitae RCV000032124 SCV000631910 pathogenic Propionyl-CoA carboxylase deficiency 2019-01-06 criteria provided, single submitter clinical testing This sequence change deletes 14 nucleotides and inserts 12 nucleotides in exon 12 of the PCCB mRNA (c.1218_1231delinsTAGAGCACAGGA), causing a frameshift at codon 407. This creates a premature translational stop signal (p.Gly407Argfs*14) and is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs750343369, ExAC 0.03%). This variant is known to be a common cause of propionic acidemia in European and South American populations (PMID: 9683601, 15464417, 2249848). Loss-of-function variants in PCCB are known to be pathogenic (PMID: 15464417). For these reasons, this variant has been classified as Pathogenic.

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