Submissions for variant NM_020166.5(MCCC1):c.137G>A (p.Gly46Glu)

gnomAD frequency: 0.00004  dbSNP: rs199517715

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000185992	SCV000281549	pathogenic	not provided	2015-10-09	criteria provided, single submitter	clinical testing
Invitae	RCV000554762	SCV000656953	likely pathogenic	3-methylcrotonyl-CoA carboxylase 1 deficiency	2023-08-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 46 of the MCCC1 protein (p.Gly46Glu). This variant is present in population databases (rs199517715, gnomAD 0.007%). This missense change has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 21071250). 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: 203797). 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 tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398925	SCV004122514	uncertain significance	not specified	2023-10-04	criteria provided, single submitter	clinical testing	Variant summary: MCCC1 c.137G>A (p.Gly46Glu) is located at a canonical splice site and results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes the canonical 3' acceptor site and two predict the variant weakens the 3' acceptor site, whereas one predicts the variant has no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 251392 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MCCC1 causing Methylcrotonyl-CoA Carboxylase Deficiency (4e-05 vs 0.0042), allowing no conclusion about variant significance. c.137G>A has been reported in the literature in the compound heterozygous state in one individual affected with Methylcrotonyl-CoA Carboxylase Deficiency (Nguyen_2011). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 21071250). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance until further functional and/or clinical evidence becomes available.