Submissions for variant NM_001258392.3(CLPB):c.1143G>A (p.Met381Ile)

gnomAD frequency: 0.00001  dbSNP: rs786205137

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000167540	SCV001413006	uncertain significance	3-methylglutaconic aciduria, type VIIB	2023-04-06	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects CLPB function (PMID: 25597510). 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. ClinVar contains an entry for this variant (Variation ID: 187783). This missense change has been observed in individual(s) with clinical features of mild 3-methylglutaconic aciduria (PMID: 25597510). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs786205137, gnomAD 0.002%). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 411 of the CLPB protein (p.Met411Ile).
GeneDx	RCV001570412	SCV001794703	likely pathogenic	not provided	2023-06-08	criteria provided, single submitter	clinical testing	Identified in a family with cataracts and neutropenia who also carried a second variant in CLPB. Parental studies were not conducted to determine if these variants were on the same (in cis) or opposite (in trans) alleles (Wortmann et al., 2015); Published functional studies suggest a damaging effect on enzymatic activity (Wortmann et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27137937, 25597510, 28687938, 27891836)
Ambry Genetics	RCV002515185	SCV003589909	uncertain significance	Inborn genetic diseases	2022-01-21	criteria provided, single submitter	clinical testing	The c.1233G>A (p.M411I) alteration is located in exon 11 (coding exon 11) of the CLPB gene. This alteration results from a G to A substitution at nucleotide position 1233, causing the methionine (M) at amino acid position 411 to be replaced by an isoleucine (I). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (2/251286) total alleles studied. The highest observed frequency was <0.01% (2/113598) of European (non-Finnish) alleles. This alteration has been reported in two affected siblings with elevated urinary excretion of 3-methylglutaconic acid, neutropenia, and cataracts (Wortmann, 2015). Another variant, p.Y617C, in CLPB was found in both patients; however, their parents were not tested to confirm if the variants were in cis or in trans. Functional studies using zebrafish showed that this alteration does not lead to changes in the integrity of the cerebellum in zebrafish embryos compared to wildtype; an in vitro assay showed that ATPase activity for this alteration was significantly decreased (Wortmann, 2015). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
OMIM	RCV000167540	SCV000218398	pathogenic	3-methylglutaconic aciduria, type VIIB	2015-02-05	no assertion criteria provided	literature only
GeneReviews	RCV000167540	SCV000328965	not provided	3-methylglutaconic aciduria, type VIIB		no assertion provided	literature only