ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 61 of the MMACHC protein (p.Arg61Trp). This variant is present in population databases (rs200483477, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with cobalamin C deficiency (PMID: 16311595, 19370762). ClinVar contains an entry for this variant (Variation ID: 203824). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MMACHC 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.

The c.181C>T (p.R61W) alteration is located in exon 2 (coding exon 2) of the MMACHC gene. This alteration results from a C to T substitution at nucleotide position 181, causing the arginine (R) at amino acid position 61 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Reported as homozygous in a patient with cobalamin C deficiency who was also homozygous for R111X (PMID: 16311595); 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: 28337550, 19370762, 16311595, 32439973)

The MMACHC c.181C>T variant is predicted to result in the amino acid substitution p.Arg61Trp. This variant has been reported in multiple individuals with methylmalonic aciduria and homocystinuria (Table 1, Lerner-Ellis et al. 2009. PubMed ID: 19370762). However, this variant has also been observed in cis with another loss-of-function MMACHC variant (p.Arg111*) in multiple individuals (Lerner-Ellis et al. 2005. PubMed ID: 16311595; Internal Data, PreventionGenetics). This variant is reported in 0.11% of alleles in individuals of European (non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Variant interpretted as Uncertain significance and reported on 12/09/2017 by GTR ID 26957. 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.