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

gnomAD frequency: 0.00025  dbSNP: rs144078282

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000167542	SCV000265562	pathogenic	3-methylglutaconic aciduria, type VIIB	2015-09-04	criteria provided, single submitter	research
GeneDx	RCV000487136	SCV000568867	pathogenic	not provided	2022-06-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with R408G resulting in little to no residual enzyme activity (Wortmann et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27290639, 28554332, 28687938, 25597510, 27891836, 34115842)
Invitae	RCV000167542	SCV000823538	pathogenic	3-methylglutaconic aciduria, type VIIB	2024-01-11	criteria provided, single submitter	clinical testing	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.
SIB Swiss Institute of Bioinformatics	RCV000167542	SCV000883174	likely pathogenic	3-methylglutaconic aciduria, type VIIB	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).
Baylor Genetics	RCV000167542	SCV001521676	likely pathogenic	3-methylglutaconic aciduria, type VIIB	2019-09-30	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000487136	SCV002023256	likely pathogenic	not provided	2019-03-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492676	SCV002781454	likely pathogenic	3-methylglutaconic aciduria, type VIIB; Neutropenia, severe congenital, 9, autosomal dominant; 3-methylglutaconic aciduria, type VIIA	2022-04-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002516522	SCV003627328	pathogenic	Inborn genetic diseases	2021-01-26	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000167542	SCV004122543	pathogenic	3-methylglutaconic aciduria, type VIIB	2023-10-05	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000167542	SCV000218400	pathogenic	3-methylglutaconic aciduria, type VIIB	2015-02-05	no assertion criteria provided	literature only
GeneReviews	RCV000167542	SCV000328964	not provided	3-methylglutaconic aciduria, type VIIB		no assertion provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000487136	SCV001959441	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000487136	SCV001963688	pathogenic	not provided		no assertion criteria provided	clinical testing