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

gnomAD frequency: 0.00012  dbSNP: rs372918203

Total submissions: 6

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000673415	SCV002255962	likely pathogenic	Cobalamin C disease	2024-02-06	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689848	SCV005185205	uncertain significance	not specified	2024-05-20	criteria provided, single submitter	clinical testing	Variant summary: MMACHC c.364C>A (p.His122Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 249448 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MMACHC causing Methylmalonic Acidemia With Homocystinuria (4e-05 vs 0.0032), allowing no conclusion about variant significance. c.364C>A has been reported in the literature in at least one homozygous individual affected with congenital disorder of glycosylation type 1A & methylmalonic aciduria cblc deficiency (e.g. Alfares_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28454995). ClinVar contains an entry for this variant (Variation ID: 557293). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV004792367	SCV005412074	uncertain significance	not provided	2024-07-17	criteria provided, single submitter	clinical testing	PP3, PM2, PM3_supporting, PM5
Fulgent Genetics, Fulgent Genetics	RCV000673415	SCV005655665	uncertain significance	Cobalamin C disease	2024-01-31	criteria provided, single submitter	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000673415	SCV001133154	likely pathogenic	Cobalamin C disease	2019-09-26	no assertion criteria provided	clinical testing