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

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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	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	2019-11-22	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.
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

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