ClinVar Genomic variation as it relates to human health

The p.Arg145X (NM_172250.2 c.433C>T) variant in MMAA has been reported in 2 het erozygous, 12 homozygous (2 of which were consanguineous) and 10 compound hetero zygous individuals with methylmalonic acidemia (Lerner-Ellis 2004, Yang 2004, Ha armann 2013, and Devi 2017). This variant has also been reported in ClinVar (Var iation ID#3160) as pathogenic by multiple laboratories. This variant has been id entified in 0.04% (6/16350) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs104893851). Although t his variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant lead s to a premature termination codon at position 145, which is predicted to lead t o a truncated or absent protein. Biallelic loss of function of the MMAA gene has been associated with methylmalonic acidemia. In summary, this variant meets cr iteria to be classified as pathogenic for methylmalonic acidemia in an autosomal recessive manner based upon its biallelic occurrence in individuals with this d isease and predicted null effect on the protein.

DNA sequence analysis of the MMAA gene demonstrated a sequence change, c.433C>T, which results in the creation of a premature stop codon at amino acid position 145, p.Arg145*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated MMAA protein with potentially abnormal function. This sequence change has previously been described in multiple individuals with methylmalonic acidemia in a homozygous or a compound heterozygous state (PMIDs: 15308131, 15523652, 23026888). This sequence change has been described in the gnomAD database with a low population frequency of 0.016% (dbSNP rs104893851).

The MMAA c.433C>T (p.Arg145Ter) nonsense variant results in the substitution of arginine at amino acid position 145 with a stop codon. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. Across a selection of the available literature, the c.433C>T variant was identified in a homozygous state in at least 13 individuals, and in a compound heterozygous state in at least 15 individuals with methylmalonic aciduria (PMID: 15523652; PMID: 22614770; PMID: 35618652). The c.433C>T variant is reported at a frequency of 0.000353 in the European (non-Finnish) population of the Genome Aggregation Database (version 3.1.2). Based on the available evidence, the c.433C>T (p.Arg145Ter) variant is classified as pathogenic for methylmalonic aciduria, cblA type.

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; This variant is associated with the following publications: (PMID: 15781192, 24095221, 16247646, 26270765, 17957493, 28497574, 26370686, 25087612, 27591164, 30609409, 30712249, 31589614, 32754920, 15523652, 23026888, 15308131)

The MMAA c.433C>T variant is predicted to result in premature protein termination (p.Arg145*). This variant is one of the most commonly reported variants causative for methylmalonic acidemia, cblA type (for example, see Lerner-Ellis et al. 2004. PubMed ID: 15523652; Yang et al. 2004. PubMed ID: 15308131; Hörster et al. 2020. PubMed ID: 32754920). This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-146560724-C-T). Nonsense variants in MMAA are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic.

This sequence change creates a premature translational stop signal (p.Arg145*) in the MMAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMAA are known to be pathogenic (PMID: 15523652, 15781192). This variant is present in population databases (rs104893851, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria due to cobalamin A deficiency (PMID: 15308131, 15523652, 16247646, 17957493, 23026888, 26270765, 27591164). ClinVar contains an entry for this variant (Variation ID: 3160). For these reasons, this variant has been classified as Pathogenic.

ACMG: PVS1, PM2_Supporting, PM3_VeryStrong, PP4

MMAA: PVS1, PM2, PM3:Supporting

Variant summary: MMAA c.433C>T variant results in a premature termination at codon 145 (274 amino acids from the end of the protein), predicted to cause a truncated or absent MMAA protein, which is a commonly known mechanism for methylmalonic academia. Mutation Taster predicts a damaging outcome for this variant; this predictions is supported by functional studies showing that patients homozygous for R145X have a "reduced ability to incorporate propionate into cellular macromolecules, an indirect measure of AdoCbl-dependent MCM activity" (10-29% of WT activity). This variant is found in 19/119564 control chromosomes at a frequency of 0.0001589, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0018257). The variant of interest has been reported in many patients from the literature, and R145X is a common disease variant that has been reported to represent 45% of pathogenic MMAA alleles (Lerner-Ellis et al. 2004). In addition, several clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this is a disease variant and was classified as pathogenic.

NM_172250.2(MMAA):c.433C>T(R145*) is classified as pathogenic in the context of methylmalonic acidemia, cblA type. Sources cited for classification include the following: PMID 15523652. Classification of NM_172250.2(MMAA):c.433C>T(R145*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

PVS1, PM3_Strong

ACMG categories: PVS1,PS1,PS4

The heterozygous variant in the MMAA gene (c.433C>T; p.Arg145*) is considered a pathogenic variant. This change represents a rare premature truncation resulting in a product 1/3 of the expected length with the last ~ 273 amino acids being truncated off. This variant has been seen previously by Yang et al (PMID: 15308131) in a one individual in a Japanese affected individuals. In the ExAC dataset this variant was seen on 19 alleles out of 121038 tested, with all tested individuals being heterozygous for the change.

The variant NM_172250.3:c.433C>T (p.Arg145Ter) in exon-2 of MMAA gene has been seen in heterozygous status. It is a nonsense variant that results in a stop codon and premature truncation of the protein. This variant has not been reported in the 1000 Genomes database and has a minor allele frequency of 0.02% in the ExAc database. The in-silico prediction of this variant is damaging by MutationTaster2.

Variant interpreted as Pathogenic and reported on 12-12-2018 by Lab or GTR ID 1006. 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.