Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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, |
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, |
RCV000586798 | SCV002017505 | pathogenic | Cobalamin C disease | 2019-12-13 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000586798 | SCV002799237 | pathogenic | Cobalamin C disease | 2022-05-25 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV000586798 | SCV004178177 | likely pathogenic | Cobalamin C disease | 2023-04-11 | criteria provided, single submitter | clinical testing | |
Natera, |
RCV001273223 | SCV001456015 | pathogenic | Methylmalonic acidemia with homocystinuria cblC | 2020-09-16 | no assertion criteria provided | clinical testing |