Submissions for variant NM_022132.5(MCCC2):c.1065A>T (p.Leu355Phe)

gnomAD frequency: 0.00011  dbSNP: rs757052602

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186003	SCV000238963	pathogenic	not provided	2021-04-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25356967, 22642865, 27033733, 21071250)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000525215	SCV000644141	pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 355 of the MCCC2 protein (p.Leu355Phe). This variant is present in population databases (rs757052602, gnomAD 0.3%). This missense change has been observed in individual(s) with 3-methylcrotonylglycinuria (PMID: 21071250, 25356967; Invitae). ClinVar contains an entry for this variant (Variation ID: 203806). 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 MCCC2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000186003	SCV000854812	likely pathogenic	not provided	2017-10-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000525215	SCV002022767	likely pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2023-07-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001271404	SCV002041770	pathogenic	Methylcrotonyl-CoA carboxylase deficiency	2021-11-23	criteria provided, single submitter	clinical testing	Variant summary: MCCC2 c.1065A>T (p.Leu355Phe) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, C-terminal domain (IPR011763) 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 0.00036 in 251280 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MCCC2 causing Methylcrotonyl-CoA Carboxylase Deficiency (0.00036 vs 0.0042), allowing no conclusion about variant significance. c.1065A>T has been reported in the literature as a homozygous genotype in multiple individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency with characteristic biochemical profiles, namely, elevated excretion of 3-hydroxyisovaleric acid (3-HIVA), 3-methylcrotonylglycine (3-MCG) and also subsequently cited by others (example, Nguyen_2011, Grunert_2012, Adhikari_2020, Shepard_2015, Fonseca_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal MCC enzyme activity in a homozygous individual. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000525215	SCV004194327	pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2024-03-30	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001271404	SCV004847363	likely pathogenic	Methylcrotonyl-CoA carboxylase deficiency	2024-01-02	criteria provided, single submitter	clinical testing	The p.Leu355Phe variant in MCCC2 has been reported in the homozygous state in at least 9 individuals and in the compound heterozygote state with another pathogenic variant in MCCC2 in 2 individuals with 3-methylcrotonyl-CoA (MCC) deficiency or a positive newborn screen (Nguyen 2011 PMID: 21071250, Shepard 2015 PMID: 25356967, Forsyth 2016 PMID: 27033733, GeneDx pers. comm., Invitae pers. comm.). Most of these individuals were typically asymptomatic at the time of testing, however had MCC deficiency determined by biochemical analyses. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 203806) and has been identified in 0.085% (13/15282) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive MCC deficiency. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PP3, PP4.
Natera, Inc.	RCV001271404	SCV001452530	pathogenic	Methylcrotonyl-CoA carboxylase deficiency	2020-09-16	no assertion criteria provided	clinical testing
Ambry Genetics	RCV002513958	SCV003717149	uncertain significance	Inborn genetic diseases	2021-07-20	flagged submission	clinical testing	Nguyen, 2011; Shepard, 2015; Forsyth, 2016 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004751353	SCV005365461	likely pathogenic	MCCC2-related disorder	2024-04-02	no assertion criteria provided	clinical testing	The MCCC2 c.1065A>T variant is predicted to result in the amino acid substitution p.Leu355Phe. This variant has been reported in the homozygous state in multiple apparently unrelated individuals with enzymatically confirmed 3-methylcrotonyl-CoA carboxylase deficiency, though it should be noted that two of these patients were asymptomatic adults (Nguyen et al. 2011. PubMed ID: 21071250; Shepard et al. 2015. PubMed ID: 25356967). It has also been reported in the heterozygous state with a second heterozygous likely pathogenic MCCC2 variant in a patient who was reportedly clinically “normal” during the neonatal period (Forsyth et al. 2016. PubMed ID: 27033733). This variant is reported in 0.26% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic or pathogenic by multiple independent submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/203806). Taken together, this variant is interpreted as likely pathogenic.