ClinVar Miner

Submissions for variant NM_022132.5(MCCC2):c.1015G>A (p.Val339Met) (rs150591260)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Miraca Genetics Laboratories, RCV000415228 SCV000328822 pathogenic 3-methylcrotonyl CoA carboxylase 2 deficiency 2016-02-29 no assertion criteria provided clinical testing Our laboratory reported dual molecular diagnoses in HEXB (NM_000521.3,c.272G>C ) and MCCC2 (NM_022132.4, c.1015G>A) in one individual with reported features of neuromuscular disease, chronic respiratory failure, cardiomyopathy and hypertension. This MCCC2 variant has been previously reported in patients affected with biotin-resistant 3-methylcrotonyl-CoA carboxylase (MCC) deficiency and functional analysis showed diminished enzyme activity of the p.V339M mutant protein [PMID 11181649, 25087612]. Additionally, our laboratory reported four molecular diagnoses in CA2 (NM_000067.2, c.232+1G>A), LARP7 (NM_001267039.1, c.1261G>A), MCCC2 (NM_022132.4, c.1015G>A), and SPG11 (NM_025137.3, c.6100C>T) in one individual with clinical features of global developmental delay, developmental regression, autistic features, intellectual disability, hypotonia, ataxia, dysmorphic features, short stature, microcephaly, hyperextensibility, failure to thrive, structural brain abnormalities, skeletal abnormalities, and limb malformation. Heterozygotes for this variant would be expected to be asymptomatic carriers.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000186002 SCV000575426 uncertain significance not provided 2017-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000186002 SCV000238962 pathogenic not provided 2018-06-22 criteria provided, single submitter clinical testing The V339M missense variant has been reported previously in association with 3-methylcrotonyl-CoA carboxylase deficiency (Wolfe et al., 2007; Grunert et al., 2012). Functional studies found that V339M is associated with approximately 4% residual enzyme activity compared to wildtype (Baumgartner et al., 2001). Furthermore, this substitution occurs at a position that is conserved across species within the carboxy transferase domain of the MCCC2 protein (Stadler et al. 2006). In summary, we interpret V339M to be pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000415228 SCV000914262 likely pathogenic 3-methylcrotonyl CoA carboxylase 2 deficiency 2019-04-05 criteria provided, single submitter clinical testing The MCCC2 c.1015G>A (p.Val339Met) missense variant has been reported in at least four studies in which it was found in at least seven individuals with 3-Methylcrotonyl-CoA carboxylase (3-MCC) deficiency, including in two individuals in a compound heterozygous state and in five individuals in a heterozygous state without a second allele detected (Baumgartner et al. 2001; Wolfe et al. 2007; Grunert et al. 2012; Morscher et al. 2012). The p.Val339Met variant was also found in a compound heterozygous state in nine asymptomatic individuals, eight of whom were identified during newborn screening and presented with biochemical markers associated with 3-MCC deficiency (Grunert et al. 2012; Fonseca et al. 2016). In addition, the variant was also detected in a compound heterozygous state in one individual in whom affected status was unknown and in a heterozygous state in one asymptomatic individual (Grunert et al. 2012; Fonseca et al. 2016). Several of the asymptomatic compound heterozygous individuals carried null alleles on the second allele (Fonseca et al. 2016). The p.Val339Met variant was absent from 200 control chromosomes (Morscher et al. 2012) and is reported at a frequency of 0.00279 in the Other population of the Genome Aggregation Database. The Val339 residue is conserved across species and expression studies in proband fibroblasts found the p.Val339Met variant resulted in 4-12% residual enzyme activity compared to wild type (Baumgartner et al. 2001; Wolfe et al. 2007). Based on the collective evidence, the p.Val399Met variant is classified as likely pathogenic for 3-MCC deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000415228 SCV000644140 pathogenic 3-methylcrotonyl CoA carboxylase 2 deficiency 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 339 of the MCCC2 protein (p.Val339Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs150591260, ExAC 0.09%). This variant has been reported in the literature in several individuals affected with 3-methylcrotonyl-CoA carboxylase (3MCC) deficiency with low MCCC2 enzymatic activity as compound heterozygous in combination with other rare variants in MCCC2 (PMID: 22642865, 27601257), and as heterozygous for individuals in whom the second variant was unknown (PMID: 11181649, 22642865, 22264772). ClinVar contains an entry for this variant (Variation ID: 203805). Experimental studies have shown that this missense change reduces the MCCC2 enzymatic activity to about 4% compared to control in vitro (PMID: 11181649). In summary, this variant is a rare missense change that has been reported in affected individuals and shown to affect protein function. For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.