ClinVar Miner

Submissions for variant NM_022132.5(MCCC2):c.599T>A (p.Ile200Asn) (rs140806722)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000153473 SCV000884097 uncertain significance not provided 2017-10-31 criteria provided, single submitter clinical testing The MCCC2 c.599T>A; p.Ile200Asn variant (rs140806722) has been reported in two asymptomatic individuals who also harbored a frameshift variant in the other MCCC2 allele; clinical information was not provided for one of these individuals, but the other had elevated 3-hydroxyisovaleric acid and 3-hydroxyisovalerylcarnitine (Grünert 2012 and Shepard 2015). The variant is reported as a variant of uncertain significance by multiple laboratories in ClinVar (Variant ID: 167278), and is found in the non-Finnish European population with an overall allele frequency of 0.39% (495/126,690 alleles, including 2 homozygotes) in the Genome Aggregation Database. The isoleucine at codon 200 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen2: benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Ile200Asn variant is uncertain at this time.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000153473 SCV000281642 uncertain significance not provided 2015-10-09 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153473 SCV000202980 uncertain significance not provided 2014-02-25 criteria provided, single submitter clinical testing
GeneDx RCV000153473 SCV000329414 uncertain significance not provided 2018-08-17 criteria provided, single submitter clinical testing The I200N variant in the MCCC2 gene has been reported in a clinically asymptomatic patient who was compound heterozygous for the I200N and a frameshift variant in MCCC2; the patient had a significantly elevated 3-hydroxyisovalerylcarnitine which was detected at 38 years after diagnosis of a child with a positive newborn screen for 3-MCC deficiency (Grünert et al., 2012). The I200N variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The I200N variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether the I200N variant is a pathogenic variant or a rare benign variant.
GenomeConnect, ClinGen RCV000509529 SCV000607235 not provided 3-methylcrotonyl CoA carboxylase 2 deficiency no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000509529 SCV000765712 likely benign 3-methylcrotonyl CoA carboxylase 2 deficiency 2017-10-03 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000509529 SCV000803540 uncertain significance 3-methylcrotonyl CoA carboxylase 2 deficiency 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for MCC2D, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:27601257).

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