ClinVar Miner

Submissions for variant NM_000282.4(PCCA):c.923dup (p.Leu308fs) (rs573607437)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000335150 SCV000382013 pathogenic Propionic acidemia 2019-04-05 criteria provided, single submitter clinical testing The PCCA c.923dupT (p.Leu308PhefsTer35) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Leu308PhefsTer35 variant has been reported in at least four studies in which it was identified in a total of 10 individuals affected with propionic acidemia, including in three in a homozygous state and in seven in a compound heterozygous state (Yang et al. 2004; Gallego-Villar et al. 2013; Witters et al. 2016; Molema et al. 2018). Control data are unavailable for the variant which is reported at a frequency of 0.000062 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Leu308PhefsTer35 variant is classified as pathogenic for propionic acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000335150 SCV001228999 pathogenic Propionic acidemia 2019-03-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu308Phefs*35) in the PCCA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs573607437, ExAC 0.006%). This variant has been observed in several individuals affected with propionic acidemia (PMID: 22033733, 20549364, 27900673, 12559849). This variant is also known as 917-923insT F307fs in the literature. ClinVar contains an entry for this variant (Variation ID: 310846). Loss-of-function variants in PCCA are known to be pathogenic (PMID: 15464417). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000335150 SCV001362337 pathogenic Propionic acidemia 2019-06-25 criteria provided, single submitter clinical testing Variant summary: PCCA c.923dupT (p.Leu308PhefsX35) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as pathogenic by our laboratory (c.937C>T, p.Arg313X). The variant allele was found at a frequency of 3.2e-05 in 250614 control chromosomes. The variant, c.923dupT, has been reported in the literature in multiple individuals affected with Propionic Acidemia (Perez_2003, Yang_2004). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One submitter have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Metabolic Disorders, Peking University First Hospital RCV000335150 SCV000929818 pathogenic Propionic acidemia 2019-05-08 no assertion criteria provided clinical testing
Counsyl RCV000335150 SCV001132451 pathogenic Propionic acidemia 2017-11-13 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001528768 SCV001741085 pathogenic not provided no assertion criteria provided clinical testing

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