ClinVar Miner

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

gnomAD frequency: 0.00011  dbSNP: rs757052602
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Total submissions: 8
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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)
Invitae 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.
Ambry Genetics RCV002513958 SCV003717149 uncertain significance Inborn genetic diseases 2021-07-20 criteria provided, single submitter clinical testing Nguyen, 2011; Shepard, 2015; Forsyth, 2016 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV000525215 SCV004194327 pathogenic 3-methylcrotonyl-CoA carboxylase 2 deficiency 2023-10-14 criteria provided, single submitter clinical testing
Natera, Inc. RCV001271404 SCV001452530 pathogenic Methylcrotonyl-CoA carboxylase deficiency 2020-09-16 no assertion criteria provided clinical testing

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