Submissions for variant NM_015506.3(MMACHC):c.566G>A (p.Arg189His)

gnomAD frequency: 0.00003  dbSNP: rs761221416

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000477781	SCV001431938	pathogenic	Cobalamin C disease	2023-03-10	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.566G>A (p.Arg189His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249560 control chromosomes (gnomAD). c.566G>A has been reported in the literature in individuals affected with Cobalamin C Disease (Methylmalonic Aciduria With Homocystinuria) (Ahrens-Nicklas_2018, Philipponnet_2020, Pajares_2021, Wang_2021). These data indicate that the variant is likely to be associated with disease. Other variants at this amino acid residue have been reported in affected individuals (PMIDs: 31279840, 16311595, 29294253) and are cited as pathogenic in ClinVar. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic and two ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477781	SCV002235664	pathogenic	Cobalamin C disease	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 189 of the MMACHC protein (p.Arg189His). This variant is present in population databases (rs761221416, gnomAD 0.02%). This missense change has been observed in individual(s) with MMACHC-related conditions (PMID: 26658511, 32164588). 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: 417857). 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. This variant disrupts the p.Arg189 amino acid residue in MMACHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16311595, 18164228, 18245139, 19760748, 24599607, 29294253). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000477781	SCV004193190	likely pathogenic	Cobalamin C disease	2024-03-20	criteria provided, single submitter	clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477781	SCV000536697	uncertain significance	Cobalamin C disease	2016-08-15	flagged submission	research
Counsyl	RCV000477781	SCV000791943	uncertain significance	Cobalamin C disease	2017-06-02	flagged submission	clinical testing