ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.658_660del (p.Lys220del) (rs398124296)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000081744 SCV000321903 pathogenic not provided 2015-11-17 criteria provided, single submitter clinical testing The c.658_660delAAG pathogenic variant in theMMACHC gene has also been reported previously in association with cblC deficiency and is reportedas a founder mutation in Chinese patients (Liu et al. 2010). The deletion causes the loss of a Lysinecodon at position 220, denoted p.Lys220del.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081744 SCV000331408 pathogenic not provided 2013-05-29 criteria provided, single submitter clinical testing
Counsyl RCV000272939 SCV000485816 pathogenic Methylmalonic acidemia with homocystinuria 2016-11-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000272939 SCV000919673 pathogenic Methylmalonic acidemia with homocystinuria 2018-10-15 criteria provided, single submitter clinical testing Variant summary: MMACHC c.658_660delAAG (p.Lys220del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 4.7e-05 in 276980 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MMACHC causing Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria) (4.7e-05 vs 0.0031), allowing no conclusion about variant significance. The variant, c.658_660delAAG has been reported in the literature in multiple Chinese individuals affected with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria) (e.g. Liu 2010, Weisfeld-Adams 2013, Wu 2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, demonstrating "decreased incorporation of label from [14C]propionate and 5-[14C]methyltetrahydrofolate into cellular macromolecules (measuring function of methylmalonylCoA mutase and methionine synthase, respectively) and decreased synthesis of both AdoCbl and MeCbl from exogenous [57Co]-labeled CNCbl. In all cases, diagnosis was confirmed by complementation analysis (Lerner-Ellis 2006)." Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000272939 SCV000935584 pathogenic Methylmalonic acidemia with homocystinuria 2018-11-12 criteria provided, single submitter clinical testing This variant, c.658_660delAAG, results in the deletion of 1 amino acid(s) of the MMACHC protein (p.Lys220del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs759243577, ExAC 0.03%). This variant has been observed in combination with another MMACHC variant in individuals affected with methylmalonic aciduria and homocystinuria (PMID: 26149271, 16311595, 21055272, 26563984, 28218226, 20631720) including individuals in whom this variant was observed on the opposite chromosome (in trans) from another pathogenic variant. This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 95707). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000272939 SCV000045077 pathogenic Methylmalonic acidemia with homocystinuria 2010-09-01 no assertion criteria provided literature only

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