ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.616C>T (p.Arg206Trp) (rs538023671)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490478 SCV000267397 uncertain significance Cobalamin C disease 2016-03-18 criteria provided, single submitter reference population
Counsyl RCV000490478 SCV000800803 likely pathogenic Cobalamin C disease 2018-01-31 criteria provided, single submitter clinical testing
Invitae RCV000490478 SCV001372575 pathogenic Cobalamin C disease 2019-10-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 206 of the MMACHC protein (p.Arg206Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with methylmalonic aciduria and homocystinuria (PMID: 16311595, 20610126, 20631720, 26149271). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203832). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg206 amino acid residue in MMACHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30157807). 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.

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