ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.440G>A (p.Gly147Asp)

dbSNP: rs140522266
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186029 SCV000238992 pathogenic not provided 2022-06-24 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); 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: 35361390, 25672861, 19700356, 16311595, 25689098, 31663237, 31503356, 26582918)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586798 SCV000699399 pathogenic Cobalamin C disease 2016-08-18 criteria provided, single submitter clinical testing Variant summary: The MMACHC c.440G>A (p.Gly147Asp) variant involves the alteration of a highly conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 3/115624 control chromosomes at a frequency of 0.0000259, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). This variant has been reported in numerous CBLC patients. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. In addition, p.Gly147Ala is also classified as pathogenic in ClinVar, suggesting Gly147 is critical for MMACHC function, which is confirmed by a functional study showed that G147D mutation was unable to bind either hydroxyl form of vitamin B12 (OHCbl) or cyano derivative (CNCbl). Taken together, this variant is classified as pathogenic.
Invitae RCV000586798 SCV000762775 pathogenic Cobalamin C disease 2023-12-31 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 147 of the MMACHC protein (p.Gly147Asp). This variant is present in population databases (rs140522266, gnomAD 0.003%). This missense change has been observed in individual(s) with methylmalonic aciduria and homocystinuria (PMID: 16311595, 16714133, 19370762, 19700356, 25672861, 26825575). 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: 203829). 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. Experimental studies have shown that this missense change affects MMACHC function (PMID: 19700356). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000586798 SCV000788961 likely pathogenic Cobalamin C disease 2017-01-13 criteria provided, single submitter clinical testing
Baylor Genetics RCV000586798 SCV001162907 pathogenic Cobalamin C disease criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000586798 SCV002017505 pathogenic Cobalamin C disease 2019-12-13 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000586798 SCV002799237 pathogenic Cobalamin C disease 2022-05-25 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000586798 SCV004178177 likely pathogenic Cobalamin C disease 2023-04-11 criteria provided, single submitter clinical testing
Natera, Inc. RCV001273223 SCV001456015 pathogenic Methylmalonic acidemia with homocystinuria cblC 2020-09-16 no assertion criteria provided clinical testing

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