ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.364C>A (p.His122Asn)

gnomAD frequency: 0.00012  dbSNP: rs372918203
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000673415 SCV000798615 uncertain significance Cobalamin C disease 2018-03-14 criteria provided, single submitter clinical testing
Invitae RCV000673415 SCV002255962 likely pathogenic Cobalamin C disease 2023-12-19 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 122 of the MMACHC protein (p.His122Asn). This variant is present in population databases (rs372918203, gnomAD 0.05%). This missense change has been observed in individual(s) with MMACHC related conditions (PMID: 28454995). ClinVar contains an entry for this variant (Variation ID: 557293). 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.His122 amino acid residue in MMACHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26253414, 31574870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City RCV000673415 SCV001133154 likely pathogenic Cobalamin C disease 2019-09-26 no assertion criteria provided clinical testing

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