Submissions for variant NM_001258392.3(CLPB):c.1792C>T (p.Arg598Cys)

gnomAD frequency: 0.00133  dbSNP: rs150343959

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000316112	SCV000344751	uncertain significance	not provided	2016-08-16	criteria provided, single submitter	clinical testing
Invitae	RCV000258954	SCV000775149	uncertain significance	3-methylglutaconic aciduria, type VIIB	2024-01-30	criteria provided, single submitter	clinical testing	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.
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000316112	SCV000920523	uncertain significance	not provided	2018-09-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000258954	SCV001523454	uncertain significance	3-methylglutaconic aciduria, type VIIB	2019-04-10	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000258954	SCV001762981	uncertain significance	3-methylglutaconic aciduria, type VIIB	2021-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000316112	SCV001795646	uncertain significance	not provided	2023-11-17	criteria provided, single submitter	clinical testing	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, 34115842, 35616898)
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000258954	SCV001981535	likely pathogenic	3-methylglutaconic aciduria, type VIIB	2021-06-01	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000316112	SCV002497155	uncertain significance	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000258954	SCV002507093	uncertain significance	3-methylglutaconic aciduria, type VIIB	2022-05-04	criteria provided, single submitter	curation	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).
PreventionGenetics, part of Exact Sciences	RCV003955419	SCV004772438	uncertain significance	CLPB-related condition	2023-11-24	criteria provided, single submitter	clinical testing	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.
GeneReviews	RCV000258954	SCV000328974	not provided	3-methylglutaconic aciduria, type VIIB		no assertion provided	literature only
OMIM	RCV000258954	SCV002559886	pathogenic	3-methylglutaconic aciduria, type VIIB	2022-08-11	no assertion criteria provided	literature only