Variant summary: The MMACHC c.331C>T (p.Arg111X) variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in vitro study showed mRNA leves in cell lines that are homozygotes for c.331C>T showed ~60% decrease compared to wild-type cell lines (Lerner-Ellis_2009), suggesting this nonsense variant leads to nonsense mediated mRNA decay. One in silico tool predicts a damaging outcome for this variant. This variant was found in 9/120818 control chromosomes at a frequency of 0.0000745, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). This variant has been shown to be one of the most common pathogenic variant in CBLC patients and tend to lead to early onset type of disease. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant has been classified as pathogenic.

The p.Arg111X variant in MMACHC has been reported in at least 29 individuals (9 homozygotes and 20 compound heterozygotes) with methymalonic aciduria and homocy stinuria, cbIC type (Lerner-Ellis 2006). It has been associated with early onset disease (Lerner-Ellis 2006). This variant has been identified in 9/120714 chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs121918242). Although this variant has been seen in the general populat ion, its frequency is low enough to be consistent with a recessive carrier frequ ency. This nonsense variant leads to a premature termination codon at position 1 11, which is predicted to lead to a truncated or absent protein. Loss of functio n of the MMACHC gene is an established disease mechanism for methymalonic acidur ia. In summary, this variant meets our criteria to be classified as pathogenic f or methymalonic aciduria and homocystinuria, cbIC type based upon its co-occurre nce with disease-causing variants in affected individuals, low frequency in cont rol populations, and predicted functional impact.

The MMACHC c.331C>T (p.R111*) variant was previously reported in the homozygous or compound heterozygous state in individuals with combined methylmalonic aciduria (also known as methylmalonic acidemia) with homocystinuria (PMID: 16714133; 18164228).

The c.331C>T variant in MMACHC is a nonsense variant predicted to introduce a stop codon at amino acid 111. This variant is expected to result in nonsense mediated decay, truncation, or a dysfunctional protein product. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 16311595). Given the available evidence, this variant is classified as Pathogenic.

NM_015506.3(MMACHC):c.331C>T (p.Arg111*) introduces a premature termination codon predicted to result in loss of normal protein function. Loss-of-function is an established mechanism of disease for this gene. This variant has been observed in affected individuals with related phenotype in a genotype context consistent with recessive disease (PMID: 16311595). This variant has been reported in individuals with related phenotype (PMID: 16311595). The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 28327205, 30609409, 16311595, 24126030, 28481040, 31503356, 30157807, 31998365, 34215320, 34426522, 32943488, 33473346, 32778825)

This sequence change creates a premature translational stop signal (p.Arg111*) in the MMACHC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMACHC are known to be pathogenic (PMID: 16311595). This variant is present in population databases (rs121918242, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria and homocystinuria, cblC type (PMID: 16311595, 16714133, 18164228, 24126030). ClinVar contains an entry for this variant (Variation ID: 1424). For these reasons, this variant has been classified as Pathogenic.

The MMACHC c.331C>T variant is predicted to result in premature protein termination (p.Arg111*). This variant has been commonly reported in the literature as causative for methylmalonic aciduria and homocystinuria, cblC type (Lerner-Ellis et al. 2009, PubMed ID: 19370762; Ricci et al. 2020. PubMed ID: 31503356). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. It has been interpreted as pathogenic by multiple independent submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1424). Nonsense variants in MMACHC are expected to be pathogenic. This variant is interpreted as pathogenic.

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Common in people of Cajun and French Canadian ancestry.