ClinVar Genomic variation as it relates to human health

Variant summary: MMACHC c.394C>T (p.Arg132X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 9.6e-05 in 249398 control chromosomes. c.394C>T has been reported in the literature in multiple individuals affected with Cobalamin C Disease (Methylmalonic Aciduria With Homocystinuria) (example, Lerner-Ellis_2009). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000962, PM2). The variant was observed in trans with a pathogenic variant (NM_015506.2:c.609G>Ap) as compound heterozygous (3billion dataset, PM3). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000001423.16). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

A Homozygote Nonsense variant c.394C>T in Exon 3 of the MMACHC gene that results in the amino acid substitution p.Arg132* was identified. The observed variant has a maximum allele frequency of 0.00010/0.00 % in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (ClinVar ID: 1423). This variant has previously been reported for cblC type of methylmalonic aciduria and homocystinuria. Functional assays in patient cell lines indicate that the p.Arg132Ter variant may result in the production of a truncated protein product with residual function (Richard E et al., 2009 and Lerner-Ellis JP et al., 2009). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

The MMACHC c.394C>T (p.Arg132Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. Across a selection of the available literature, the p.Arg132Ter variant is found in at least 57 individuals with the cblC type of methylmalonic aciduria and homocystinuria, the most common inborn error of cobalamin metabolism, including in a homozygous state in at least 31 individuals and in a compound heterozygous state in 26 individuals (Lerner-Ellis et al. 2006; Richard et al. 2009; Lerner-Ellis et al. 2009; Liu et al. 2010; Kılıç et al. 2013). Additionally, this variant has been identified in 20% of disease alleles in individuals from India, Pakistan, and Middle East, and in 5.7% of disease alleles in Chinese population (Lerner-Ellis et al. 2006; Lerner-Ellis et al. 2009; Liu et al. 2010). The p.Arg132Ter variant is associated with late onset disease characterized by acute neurological deterioration without systemic symptoms (Lerner-Ellis et al. 2006). The p.Arg132Ter variant was absent from 155 control subjects (Lerner-Ellis et al. 2006; Lerner-Ellis et al. 2009) but is reported at a frequency of 0.000719 in the South Asian population of the Genome Aggregation Database. Functional assays in patient cell lines indicate that the p.Arg132Ter variant may result in the production of a truncated protein product with residual function (Lerner-Ellis et al. 2009). Furthermore, patient skin fibroblasts do not show an increase in reactive oxygen species levels compared to control cells, however, there was an increase in basal level of apoptosis (Richard et al. 2009). Based on the collective evidence and application of the ACMG criteria, the p.Arg132Ter variant is classified as pathogenic for disorders of intracellular cobalamin metabolism.

Reported that many individuals with the R132X variant are of Middle Eastern origin (Lerner-Ellis et al., 2006, Lerner-Ellis et al., 2009); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 151 amino acids are lost; This variant is associated with the following publications: (PMID: 27252276, 27324188, 27629047, 27905001, 17431913, 24577983, 20631720, 25511120, 25525159, 26563984, 26149271, 19760748, 16311595, 27591164, 28218226, 29374341, 28693988, 19370762, 16714133, 23891399, 29581464, 29961769, 30712249, 31203424, 31697851, 31503356, 30157807, 29731766, 31589614, 33083013, 32943488, 32901917)

PM2, PM3, PS4, PVS1

This sequence change creates a premature translational stop signal (p.Arg132*) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 151 amino acid(s) of the MMACHC protein. This variant is present in population databases (rs121918241, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with methylmalonic acidemia and hyperhomocysteinemia of the cobalamin C (cblC) type (PMID: 16311595, 19760748, 20631720, 24577983, 25511120, 26149271, 26563984). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1423). For these reasons, this variant has been classified as Pathogenic.

The observed stop gained variant c.394C>T(p.Arg132Ter) in MMACHC gene has been reported previously in homozygous and compound heterozygous state in multiple individuals with methylmalonic acidemia and hyperhomocysteinemia of the cobalamin C (cblC) type (Han B, et al., 2016, Zong Y, et al., 2015). Experimental studies show that functional assays in patient cell lines indicate that the p.Arg132Ter variant may result in the production of a truncated protein product with residual function (Lerner-Ellis et al., 2009) and also showed an increase in basal level of apoptosis (Richard et al. 2009). The c.394C>T variant is reported with 0.01% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing.For these reasons, this variant has been classified as Pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with methylmalonic aciduria and homocystinuria, cblC type (MIM#277400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (24 heterozygotes, 0 homozygotes). (SP) 0701 - Many other protein truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The p.Arg132* variant in the MMACHC gene has been previously reported in the homozygous or compound heterozygous state in at least 35 individuals with cobalamin C deficiency (Lerner-Ellis et al., 2006; Nogueira et al., 2008; Lerner-Ellis et al., 2009; Ricci et al., 2020). In one affected cohort, the p.Arg132* variant accounted for 20% of the pathogenic alleles identified and was associated with later onset of disease (Lerner-Ellis et al., 2009). This variant has also been identified in 22/30,600 (0.07%) South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The p.Arg132* variant leads to a premature stop codon in exon 3 of 4 coding exons, and is therefore predicted to undergo nonsense-mediated decay resulting in a truncated or absent protein. Homozygous or compound heterozygous loss of function is an established mechanism of disease for the MMACHC gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg132* variant as pathogenic for autosomal recessive cobalamin C deficiency based on the information above. [ACMG evidence codes used: PVS1; PM3_Very Strong; PM2]

Common in people of Indian and Middle Eastern ancestry associated with a late-onset phenotype