ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.80A>G (p.Gln27Arg)

gnomAD frequency: 0.00001  dbSNP: rs546099787
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667730 SCV000792226 pathogenic Cobalamin C disease 2017-06-13 criteria provided, single submitter clinical testing
Invitae RCV000667730 SCV000941526 pathogenic Cobalamin C disease 2024-01-08 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 27 of the MMACHC protein (p.Gln27Arg). This variant is present in population databases (rs546099787, gnomAD 0.02%). This missense change has been observed in individual(s) with methylmalonic aciduria and/or homocystinuria, cblC type (PMID: 20924684, 28327205). 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: 552467). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000667730 SCV004029139 pathogenic Cobalamin C disease 2023-07-26 criteria provided, single submitter clinical testing Variant summary: MMACHC c.80A>G (p.Gln27Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Computational tools predict no significant impact on normal splicing. However, to our knowledge, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 249530 control chromosomes (gnomAD). c.80A>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Methylmalonic Acidemia With Homocystinuria and it has been suggested that it is a founder variant in individuals of Chinese ancestry (e.g. Lerner-Ellis_2006, Liu_2010). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16311595, 20631720). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab RCV000667730 SCV004178127 pathogenic Cobalamin C disease 2023-04-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV000667730 SCV004193167 pathogenic Cobalamin C disease 2023-10-17 criteria provided, single submitter clinical testing
Natera, Inc. RCV001272218 SCV001453987 pathogenic Methylmalonic acidemia with homocystinuria cblC 2020-09-16 no assertion criteria provided clinical testing

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