ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.440G>C (p.Gly147Ala) (rs140522266)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000576585 SCV000678166 likely pathogenic Methylmalonic acidemia with homocystinuria 2016-12-28 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000576585 SCV000894026 pathogenic Methylmalonic acidemia with homocystinuria 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000186028 SCV000238991 pathogenic not provided 2015-09-03 criteria provided, single submitter clinical testing This variant is denoted p.Gly147Ala (GGT>GCT): c.440 G>C in exon 4 of the MMACHC gene (NM_015506.2). The G147A missense mutation has been reported previously in association with cblC deficiency (Lerner-Ellis et al., 2006). In a series of 204 individuals with cblC deficiency, the G147A mutation was detected on 3 MMACHC alleles (Lerner-Ellis et al., 2006). The variant is found in MMA-MET panel(s).
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000576585 SCV000746399 pathogenic Methylmalonic acidemia with homocystinuria 2017-12-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000262040 SCV000357927 likely pathogenic Disorders of Intracellular Cobalamin Metabolism 2017-04-27 criteria provided, single submitter clinical testing The MMACHC c.440G>C (p.Gly147Ala) missense variant has been reported in five studies in which it is found in at least five individuals with the cblC type of disorders of intracellular cobalamin metabolism, including in two in a homozygous state and in three in a compound heterozygous state (Lerner-Ellis et al. 2006; Morel et al. 2006; Lerner-Ellis et al. 2009; Yamamoto et al. 2015; Brookes et al. 2016). The variant was also found in one asymptomatic individual identified through newborn screening (Scolamiero et al. 2015). The p.Gly147Ala variant was absent from 155 control samples but is reported at a frequency of 0.00073 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence from the literature the p.Gly147Ala variant is classified as likely pathogenic for disorders of intracellular cobalamin metabolism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000576585 SCV000699400 pathogenic Methylmalonic acidemia with homocystinuria 2017-06-23 criteria provided, single submitter clinical testing Variant summary: The MMACHC c.440G>C (p.Gly147Ala) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict damaging outcome for this variant. This variant was found in 52/115728 control chromosomes (including ExAC) at a frequency of 0.0004493, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). This variant has been reported in multiple patients both homozygously and compound heterozygously. Another missense change at the same residue (Gly147Glu) is known pathogenic variant, suggesting that codon Gly147 is mutational hot-spot and is critical for protein function. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000576585 SCV000762781 pathogenic Methylmalonic acidemia with homocystinuria 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 147 of the MMACHC protein (p.Gly147Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs140522266, ExAC 0.07%). This variant has been reported in individuals affected with methylmalonic aciduria and homocystinuria, generally with mild or late-onset disease (PMID: 19370762, 25689098, 26825575). ClinVar contains an entry for this variant (Variation ID: 203828). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Gly147Asp) has been determined to be pathogenic (PMID: 19370762, 19700356). This suggests that the glycine residue is critical for MMACHC protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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