Submissions for variant NM_020166.5(MCCC1):c.1331G>A (p.Arg444His)

gnomAD frequency: 0.00004  dbSNP: rs768785753

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808142	SCV000948235	pathogenic	3-methylcrotonyl-CoA carboxylase 1 deficiency	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 444 of the MCCC1 protein (p.Arg444His). This variant is present in population databases (rs768785753, gnomAD 0.04%). This missense change has been observed in individual(s) with MCCC1-related conditions (PMID: 25382614, 26566957). 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: 203796). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MCCC1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001275506	SCV004037606	likely pathogenic	Methylcrotonyl-CoA carboxylase deficiency	2023-08-03	criteria provided, single submitter	clinical testing	Variant summary: MCCC1 c.1331G>A (p.Arg444His) results in a non-conservative amino acid change located in the Biotin carboxylase, C-terminal domain (IPR005482) 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 2.8e-05 in 251422 control chromosomes. c.1331G>A has been reported in the literature in both homozygous and compound heterozygous individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency (e.g. Yang_2015, Rips_2016, Lin_2019, Navarrete_2019, Martin-Rivada_2022, Zhou_2022). These data indicate that the variant is likely to be associated with disease. 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: 30904546, 35281663, 30626930, 26566957, 25382614, 35664874). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000808142	SCV004194253	likely pathogenic	3-methylcrotonyl-CoA carboxylase 1 deficiency	2024-03-26	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV003480081	SCV004226552	pathogenic	not provided	2024-05-28	criteria provided, single submitter	clinical testing	PP3, PP4, PM2_moderate, PM3_strong, PS4_moderate
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000808142	SCV005416952	likely pathogenic	3-methylcrotonyl-CoA carboxylase 1 deficiency		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Moderate+PM3+PP4
Fulgent Genetics, Fulgent Genetics	RCV000808142	SCV005661952	likely pathogenic	3-methylcrotonyl-CoA carboxylase 1 deficiency	2024-04-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001275506	SCV001460691	uncertain significance	Methylcrotonyl-CoA carboxylase deficiency	2020-09-16	no assertion criteria provided	clinical testing
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV000808142	SCV004800862	uncertain significance	3-methylcrotonyl-CoA carboxylase 1 deficiency		no assertion criteria provided	clinical testing	PM3_S+PP3