Submissions for variant NM_020166.5(MCCC1):c.1115A>C (p.Gln372Pro)

dbSNP: rs755328329

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001061122	SCV001225854	likely pathogenic	3-methylcrotonyl-CoA carboxylase 1 deficiency	2023-02-16	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 372 of the MCCC1 protein (p.Gln372Pro). This variant is present in population databases (rs755328329, gnomAD 0.0009%). This missense change has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 14680978, 26566957; Invitae). 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: 855786). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MCCC1 protein function. 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	RCV002282445	SCV002571937	uncertain significance	not specified	2022-08-01	criteria provided, single submitter	clinical testing	Variant summary: MCCC1 c.1115A>C (p.Gln372Pro) results in a non-conservative amino acid change located in the biotin carboxylation domain (IPR011764) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251426 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1115A>C has been reported in the literature in individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency, including three individuals of Bukharian Jewish ancestry (e.g. Desviat_2003, Rips_2016). However these reports include at least one asymptomatic individual and do not present strong evidence for causality. Therefore, they do not provide unequivocal conclusions about association of the variant with Methylcrotonyl-CoA Carboxylase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted an assessment for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003906167	SCV004725400	uncertain significance	MCCC1-related condition	2024-01-22	criteria provided, single submitter	clinical testing	The MCCC1 c.1115A>C variant is predicted to result in the amino acid substitution p.Gln372Pro. This variant was reported in individuals with 3-methylcrotonyl-CoA carboxylase deficiency (Desviat et al. 2003. PubMed ID: 14680978; Rips et al. 2016. PubMed ID: 26566957). However, in one individual no second variant was identified (patient 16255 in Desviat et al. 2003. PubMed ID: 14680978) and one individual, who also harbored another pathogenic MCCC1 variant, was asymptomatic (M(B18) in Rips et al. 2016. PubMed ID: 26566957). This variant is reported in 0.00088% 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.