ClinVar Genomic variation as it relates to human health

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

The heterozygous p.Arg628Cys variant in CLPB was identified by our study in the compound heterozygous state, along with another variant of uncertain significance, in 1 individual with 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia. The variant has been reported in 2 British siblings with 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia (PMID: 25595726), and has been identified in 0.2% (239/128136) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs150343959). This variant has also been reported in ClinVar (Variation ID: 279610) as pathogenic by GeneReviews, and as having uncertain significance by Invitae, EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, and Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes. In vitro functional studies provide some evidence that the p.Arg628Cys variant may impact protein function (PMID: 25595726). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with reported variants of uncertain significance, and in 2 individuals with 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia increases the likelihood that the p.Arg628Cys variant is pathogenic (VariationID: 279611; PMID: 25595726). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_moderate, PP3, PM3_supporting, BS1 (Richards 2015).

The c.1792C>T (p.Arg598Cys) variant in CLPB was seen in a patient with congenital cataracts and 3-methylglutaconic aciduria confirmed via urine organic acids (internal data). Parental phasing demonstrated that this variant was in the trans configuration with a likely pathogenic CLPB frameshift variant in the affected proband. An unaffected sibling also carries this variant but NOT the frameshift variant. The two heterozygous family members for this variant had intermediate levels of 3-methylglutaconic acid, as did the parent with the pathogenic frameshift variant. This variant is predicted to impact a critical residue for salt bridge formation (PMID:25595726), and in silico models predict a pathogenic effect. Given the population frequency (present in 3293 alleles including 4 homozygotes in gnomad v4.0.0), it may be possible that this variant is hypomorphic, and may only be clinically significant when present in the trans configuration with a null variant.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 628 of the CLPB protein (p.Arg628Cys). This variant is present in population databases (rs150343959, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of 3-methylglutaconic aciduria (PMID: 25595726, 34115842, 35616898). ClinVar contains an entry for this variant (Variation ID: 279610). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on CLPB function (PMID: 25595726). 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.

Variant summary: CLPB c.1882C>T (p.Arg628Cys) results in a non-conservative amino acid change located in the Clp ATPase, C-terminal domain (IPR019489) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 1610442 control chromosomes, predominantly at a frequency of 0.0026 within the Non-Finnish European subpopulation in the gnomAD database, including 4 homozygotes, strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1882C>T has been reported in the literature in the compound heterozygous state in individuals affected with and/or with clinical features of 3-Methylglutaconic Aciduria, Type VIIB (e.g. Kanabus_2015, Rivalta_2022, Denomme-Pichon_2022). These data indicate that the variant may be associated with disease. It has also been reported in the heterozygous state in three unrelated individuals affected with congenital neutropenia, without strong evidence for causality (e.g. Warren_2022). One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g. Kanabus_2015). The following publications have been ascertained in the context of this evaluation (PMID: 34782754, 25595726, 34115842, 35616898). ClinVar contains an entry for this variant (Variation ID: 279610). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

Classified as a variant of uncertain significance and identified heterozygous in three individuals with cyclic neutropenia (PMID: 34115842); 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: 28687938, 25595726, 27891836, 34782754, 36074910, 35616898, 35493704, Weronika2023[poster], 34115842)

Unlikely to be causative of CLPB-related congenital neutropenia with or without neurodevelopmental disorders (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

The CLPB c.1882C>T variant is predicted to result in the amino acid substitution p.Arg628Cys. This variant has been reported in the compound heterozygous state in two siblings with 3-methylglutaconic aciduria, renal cysts, nephrocalcinosis, and cataracts (Kanabus et al. 2015. PubMed ID: 25595726) and in the heterozygous state without a second variant in three unrelated patients with cyclic neutropenia (Warren et al. 2022. PubMed ID: 34115842). This variant is reported in 0.19% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.