ClinVar Genomic variation as it relates to human health

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with 3-methylcrotonyl-CoA carboxylase deficiency who was asymptomatic and had a 2nd MCCC1 variant identified, but segregation information was not provided (Shepard et al., 2015); This variant is associated with the following publications: (PMID: 25356967)

Variant summary: MCCC1 c.1894C>T (p.Pro632Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 251318 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MCCC1 causing Methylcrotonyl-CoA Carboxylase Deficiency (0.0004 vs 0.0042), allowing no conclusion about variant significance. c.1894C>T has been reported in the literature in at least a compound heterozygous individual affected with Methylcrotonyl-CoA Carboxylase Deficiency (example: Shepard_2015). These data do not allow any conclusion about variant significance. 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: 27601257, 25356967, 30887117, 38374194). ClinVar contains an entry for this variant (Variation ID: 344304). Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 632 of the MCCC1 protein (p.Pro632Ser). This variant is present in population databases (rs142867987, gnomAD 0.2%). This missense change has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase (3MCC) deficiency (PMID: 25356967). ClinVar contains an entry for this variant (Variation ID: 344304). 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 MCCC1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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.