Submissions for variant NM_020166.5(MCCC1):c.295G>A (p.Gly99Ser)

gnomAD frequency: 0.00002  dbSNP: rs375244642

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000812667	SCV000952989	likely pathogenic	3-methylcrotonyl-CoA carboxylase 1 deficiency	2023-07-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 99 of the MCCC1 protein (p.Gly99Ser). This variant is present in population databases (rs375244642, gnomAD 0.02%). This missense change has been observed in individual(s) with 3 Methylcrotonyl-CoA carboxylase deficiency (PMID: 25190158, 31730530; 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: 656280). 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) performed at Invitae indicates that this missense variant is expected to disrupt 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	RCV003323730	SCV004029601	uncertain significance	not specified	2023-07-21	criteria provided, single submitter	clinical testing	Variant summary: MCCC1 c.295G>A (p.Gly99Ser) results in a non-conservative amino acid change located in the biotin carboxylase-like, N-terminal domain (IPR005481) 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 2.4e-05 in 251214 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.295G>A has been reported in the literature in two individuals identified through newborn screening programs as affected with Methylcrotonyl-CoA Carboxylase Deficiency, including at least one case where it was found in trans with a pathogenic variant (e.g. Ye_2014, Wang_2019, Yang_2019). These data do not allow any strong conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31730530, 30838026, 25190158). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000812667	SCV002079123	uncertain significance	3-methylcrotonyl-CoA carboxylase 1 deficiency	2020-01-23	no assertion criteria provided	clinical testing