ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.440G>A (p.Gly147Asp) (rs140522266)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000586798 SCV000788961 likely pathogenic Methylmalonic acidemia with homocystinuria 2017-01-13 criteria provided, single submitter clinical testing
GeneDx RCV000186029 SCV000238992 pathogenic not provided 2018-02-21 criteria provided, single submitter clinical testing This variant is denoted p.Gly147Asp (GGT>GAT): c.440 G>A in exon 4 of the MMACHC gene (NM_015506.2). The G147D missense mutation in the MMACHC gene has been reported previously in association with cblC deficiency (Lerner-Ellis et al., 2006). In a series of 204 individuals with cblC deficiency, the G147D mutation was detected on 9 MMACHC alleles (Lerner-Ellis et al., 2006). The variant is found in MMA-MET panel(s).
Integrated Genetics/Laboratory Corporation of America RCV000586798 SCV000699399 pathogenic Methylmalonic acidemia with homocystinuria 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 Methylmalonic acidemia with homocystinuria 2018-03-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 147 of the MMACHC protein (p.Gly147Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs140522266, ExAC 0.005%). This variant has been observed as homozygous or in combination (in trans) with another MMACHC pathogenic variant in individuals affected with methylmalonic aciduria and homocystinuria (PMID: 16311595, 16714133, 19370762, 19700356, 25672861, 26825575). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 203829). Experimental studies have shown that this missense change reduces the protein:protein interaction of MMACHC with cyanocobalamin and hydroxocobalamin (PMID: 19700356). For these reasons, this variant has been classified as Pathogenic.

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