ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.388T>C (p.Tyr130His)

gnomAD frequency: 0.00001  dbSNP: rs372670428
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV001004152 SCV001162902 pathogenic Cobalamin C disease 2023-12-19 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001004152 SCV001588706 pathogenic Cobalamin C disease 2023-10-23 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 130 of the MMACHC protein (p.Tyr130His). This variant is present in population databases (rs372670428, gnomAD 0.006%). This missense change has been observed in individual(s) with cobalamin C deficiency (PMID: 16311595, 18164228, 28835862, 31470807). ClinVar contains an entry for this variant (Variation ID: 813350). 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.Tyr130 amino acid residue in MMACHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19370762, 24210589). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001004152 SCV002547476 pathogenic Cobalamin C disease 2022-05-25 criteria provided, single submitter clinical testing Variant summary: MMACHC c.388T>C (p.Tyr130His) 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 1.6e-05 in 249424 control chromosomes (gnomAD). c.388T>C has been reported in the literature in compound heterozygosity with known pathogenic MMACHE variants in individuals affected with Methylmalonic Acidemia With Homocystinuria (Lerner-Ellis_2006, Nogueira_2008, Ardissino_2017, Grandone_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV001004152 SCV002810904 likely pathogenic Cobalamin C disease 2022-01-25 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001004152 SCV004178163 likely pathogenic Cobalamin C disease 2023-04-11 criteria provided, single submitter clinical testing

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