ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.352del (p.Gln118fs) (rs749264632)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506122 SCV000604239 pathogenic not specified 2017-03-17 criteria provided, single submitter clinical testing
GeneDx RCV000627427 SCV000748425 pathogenic not provided 2018-05-02 criteria provided, single submitter clinical testing The c.352delC pathogenic variant in the MMACHC gene has been reported previously either in the homozygous state or in combination with another MMACHC variant in multiple individuals with methylmalonic aciduria and homocystinuria, cobalamin C type (Lerner-Ellis et al., 2006; Whitaker et al., 2017; Gilson et al., 2018). The c.352delC variant causes a frameshift starting with codon Glutamine 118, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Gln118ArgfsX6. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.352delC variant is observed in 8/33,578 (0.02%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). We interpret c.352delC as a pathogenic variant.
Invitae RCV000641152 SCV000762774 pathogenic Methylmalonic acidemia with homocystinuria 2018-10-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln118Argfs*6) in the MMACHC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs749264632, ExAC 0.03%). This variant has been reported in several individuals affected with methylmalonic aciduria and homocystinuria, although the second alleles in these individuals were not reported (PMID: 16311595). Loss-of-function variants in MMACHC are known to be pathogenic (PMID: 16311595). For these reasons, this variant has been classified as Pathogenic.

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