ClinVar Miner

Submissions for variant NM_001258392.3(CLPB):c.1132A>G (p.Arg378Gly) (rs144078282)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487136 SCV000568867 likely pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing The R408G variant in the CLPB gene has been previously reported in three individuals from the same family with hypotonia, neonatal hypoglycemia, microcephaly, and elevated levels of 3-methylglutaconic acid who are also heterozygous for another variant in the CLPB gene, R417X; however, the phase of the two variants is unknown (Wortmann et al., 2015). Furthermore, functional analysis suggest that the R408G variant results in little to no residual enzyme activity (Wortmann et al., 2015). The R408G variant is observed in 21/66688 (0.03%) alleles from individuals of European Non-Finnish background in the ExAC dataset (Lek et al., 2016). The R408G 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. This substitution occurs at a position that is conserved across species. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
GeneReviews RCV000167542 SCV000328964 pathogenic 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia 2016-09-14 no assertion criteria provided literature only
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000167542 SCV000265562 pathogenic 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia 2015-09-04 criteria provided, single submitter research
Invitae RCV000167542 SCV000823538 pathogenic 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia 2018-10-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 408 of the CLPB protein (p.Arg408Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs144078282, ExAC 0.03%). This variant has been reported to segregate with 3-methylglutaconic aciduria in a family (PMID: 25597510). It has also been reported in several unrelated affected individuals (PMID: 28554332, 27290639, 28687938). ClinVar contains an entry for this variant (Variation ID: 187785). Experimental studies have shown that this missense change disrupts CLPB enzymatic activity in vitro (PMID: 25597510). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000167542 SCV000218400 pathogenic 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia 2015-02-05 no assertion criteria provided literature only
SIB Swiss Institute of Bioinformatics RCV000167542 SCV000883174 likely pathogenic 3-methylglutaconic aciduria with cataracts, neurologic involvement, and neutropenia 2018-10-15 criteria provided, single submitter curation This variant is interpreted as Likely Pathogenic, for 3-methylglutaconic aciduria with cataracts, neurologic involvement and neutropenia, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/25597510).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.