ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.80A>G (p.Gln27Arg) (rs546099787)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667730 SCV000792226 pathogenic Methylmalonic acidemia with homocystinuria 2017-06-13 criteria provided, single submitter clinical testing
Invitae RCV000667730 SCV000941526 pathogenic Methylmalonic acidemia with homocystinuria 2018-07-12 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 27 of the MMACHC protein (p.Gln27Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs546099787, ExAC 0.02%). This variant has been observed on the opposite chromosome (in trans) from other pathogenic variants in individuals affected with methylmalonic aciduria and homocystinuria, cblC type (PMID: 28327205, 20924684). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. It is a common variant in the Chinese population and has also been reported in several homozygous and compound heterozygous individuals affected with methylmalonic aciduria and homocystinuria, cblC type (PMID: 16311595, 26412180, 29042959, 16714133). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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