Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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 |