ClinVar Miner

Submissions for variant NM_000532.5(PCCB):c.484G>T (p.Gly162Trp) (rs754752068)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000634872 SCV000756226 uncertain significance Propionic acidemia 2019-08-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with tryptophan at codon 162 of the PCCB protein (p.Gly162Trp). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and tryptophan. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in an individual affected with propionic acidemia (Invitae). ClinVar contains an entry for this variant (Variation ID: 529437). 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. This variant disrupts the p.Gly162 amino acid residue in PCCB. Other variant(s) that disrupt this residue have been observed in individuals with PCCB-related conditions (PMID: 19099776), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193212 SCV001361919 uncertain significance not specified 2020-12-21 criteria provided, single submitter clinical testing Variant summary: PCCB c.484G>T (p.Gly162Trp) results in a non-conservative amino acid change located in the N-terminal domain (IPR011762) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 171574 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.484G>T has been reported in the literature (Adhikari_2020) and in the ClinVar database (SCV000756226.3) in individual(s) affected with Propionic Acidemia. Furthermore, a different variant affecting the same amino acid residue (c.484G>A, p.Gly162Arg) has been reported in the literature in affected individuals (PMID: 19099776) and is cited in online databases as pathogenic/disease-associated (HGMD, LOVD), suggesting that the Gly162 residue is important for protein function. These data suggest that c.484G>T may be associated with Propionic Acidemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics RCV000634872 SCV001526098 pathogenic Propionic acidemia 2018-01-27 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. Both variants have been previously reported as disease-causing [PMID 12559849, 19099776]

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