ClinVar Miner

Submissions for variant NM_000532.5(PCCB):c.1229G>A (p.Arg410Gln)

gnomAD frequency: 0.00004  dbSNP: rs778742647
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000673426 SCV000798627 uncertain significance Propionic acidemia 2018-03-15 criteria provided, single submitter clinical testing
Invitae RCV000673426 SCV000960283 pathogenic Propionic acidemia 2023-11-05 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 410 of the PCCB protein (p.Arg410Gln). This variant is present in population databases (rs778742647, gnomAD 0.03%). This missense change has been observed in individual(s) with propionic acidemia (PMID: 19238581, 24916042). ClinVar contains an entry for this variant (Variation ID: 557302). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PCCB protein function. This variant disrupts the p.Arg410 amino acid residue in PCCB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8411997, 12007220, 12757933, 15890657, 15949719, 22033733). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000673426 SCV004202918 likely pathogenic Propionic acidemia 2024-02-24 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000673426 SCV004847428 likely pathogenic Propionic acidemia 2024-02-02 criteria provided, single submitter clinical testing The p.Arg430Gln variant in PCCB has been reported in the homozygous and compound heterozygous state in 2 individuals with propionic acidemia (Lee 2009 PMID: 19238581, Laemmle 2014 PMID: 24916042). These individuals had low levels of enzyme activity. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 557302) and has been identified in 0.02% (1/5200) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. Another variant involving this codon (p.Arg430Trp) has been identified in individuals with propionic acidemia and has been classified as pathogenic by multiple clinical laboratories in ClinVar. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive propionic acidemia. ACMG/AMP Criteria applied: PM3, PM5, PP4, PM2_Supporting, PP3.
Natera, Inc. RCV000673426 SCV001454526 likely pathogenic Propionic acidemia 2020-09-16 no assertion criteria provided clinical testing

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