ClinVar

Description

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.