ClinVar Genomic variation as it relates to human health

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 408 of the CLPB protein (p.Arg408Gly). This variant is present in population databases (rs144078282, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive 3-methylglutaconic aciduria (PMID: 25597510, 27290639, 28554332, 28687938). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 187785). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CLPB function (PMID: 25597510). For these reasons, this variant has been classified as Pathogenic.

The c.1222A>G (p.R408G) alteration is located in exon 11 (coding exon 11) of the CLPB gene. This alteration results from an A to G substitution at nucleotide position 1222, causing the arginine (R) at amino acid position 408 to be replaced by a glycine (G). Based on data from the Genome Aggregation Database (gnomAD) database, the CLPB c.1222A>G alteration was observed in 0.02% (58/282666) of total alleles studied, with a frequency of 0.04% (51/129018) in the European (non-Finnish) subpopulation. This alteration has been confirmed in trans with a second disease-causing allele in multiple individuals with 3-methylglutaconic aciduria, developmental delay/intellectual disability, microcephaly, neutropenia, and/or cataracts (Wortmann, 2015; Pronicka, 2016; Pronicka, 2017; Bowling, 2017). This amino acid position is highly conserved in available vertebrate species. In vitro analysis revealed this alteration leads to reduced ATPase activity as compared to wild-type protein (Wortmann, 2015). The in silico prediction for the p.R408G alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Variant summary: CLPB c.1222A>G (p.Arg408Gly) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) 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 0.0002 in 251282 control chromosomes (gnomAD). c.1222A>G has been reported in the literature in multiple bi-allelic individuals affected with autosomal recessive 3-Methylglutaconic Aciduria (examples: Wortmann_2015 and Pronicka_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Wortmann_2015). The following publications have been ascertained in the context of this evaluation (PMID: 28687938, 25597510). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 25597510); This variant is associated with the following publications: (PMID: 27290639, 28554332, 28687938, 25597510, 27891836, 34115842, 36170828, 36745679)

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).