ClinVar Miner

Submissions for variant NM_000282.4(PCCA):c.425G>A (p.Gly142Asp) (rs796052019)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186085 SCV000239109 pathogenic not provided 2018-11-08 criteria provided, single submitter clinical testing The G142D variant in the PCCA gene has been reported as homozygous in several unrelated individuals with propionic acidemia and is a common pathogenic variant in the Saudi population (Shuaib et al., 2012; AlGhamdi et al., 2018). The G142D variant is not observed in large population cohorts (Lek et al., 2016). The G142D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, we interpret G142D to be a pathogenic variant.
Pathology and Clinical Laboratory Medicine,King Fahad Medical City RCV000414788 SCV000996285 pathogenic Propionic acidemia criteria provided, single submitter clinical testing Compatible metabolite assay
Invitae RCV000414788 SCV001401517 likely pathogenic Propionic acidemia 2019-10-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 142 of the PCCA protein (p.Gly142Asp). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in the homozygous state in many individuals of Saudi descent affected with propionic acidemia (PMID: 22156789, 30705822). ClinVar contains an entry for this variant (Variation ID: 203880). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Gly142 amino acid residue in PCCA. Other variant(s) that disrupt this residue have been observed in individuals with PCCA-related conditions (PMID: 30274917), which suggests that this may be a clinically significant amino acid residue. 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.
Baylor Genetics RCV000414788 SCV000328820 likely pathogenic Propionic acidemia 2014-08-19 no assertion criteria provided clinical testing Our laboratory has reported dual molecular diagnoses in AGL (NM_000028.2, c.4353G>T) and PCCA (NM_000282.3, c.425G>A) in this individual who has reported features of delayed motor milestones, delayed speech, hypotonia, short stature, failure to thrive, hepatomegaly, and elevated liver enzymes. The PCCA variant has been previously reported, but there is not sufficient information to categorize it as disease-causing (PMID:22156789). Heterozygotes for this variant would be expected to be asymptomatic carriers.
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000414788 SCV001133014 pathogenic Propionic acidemia 2019-09-26 no assertion criteria provided clinical testing

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