ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.481C>T (p.Arg161Ter) (rs370596113)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000081739 SCV000329426 pathogenic not provided 2018-11-26 criteria provided, single submitter clinical testing The R161X nonsense variant in the MMACHC gene has been reported previously in association with cblC deficiency (Lerner-Ellis, et al., 2006). This pathogenic variant is predicted to cause loss of normal protein function through protein truncation.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081739 SCV000331416 pathogenic not provided 2013-06-06 criteria provided, single submitter clinical testing
Counsyl RCV000340205 SCV000486526 pathogenic Methylmalonic acidemia with homocystinuria 2016-11-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000340205 SCV000919671 pathogenic Methylmalonic acidemia with homocystinuria 2018-01-08 criteria provided, single submitter clinical testing Variant summary: The MMACHC c.481C>T (p.Arg161X) variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.609G>A, p.Trp203X; c.615C>G, p.Tyr205X; c.666C>A, p.Tyr222X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 6/276988 control chromosomes (gnomAD) at a frequency of 0.0000217, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). The variant has been reported in numerous affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000340205 SCV000934746 pathogenic Methylmalonic acidemia with homocystinuria 2018-12-05 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MMACHC gene (p.Arg161*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 122 amino acids of the MMACHC protein. This variant is present in population databases (rs370596113, ExAC 0.006%). This variant has been observed in individuals affected with methylmalonic aciduria and homocystinuria (PMID: 16311595, 20631720). ClinVar contains an entry for this variant (Variation ID: 95703). This variant disrupts the C-terminus of the MMACHC protein. Another variant that disrupts this region (p.Val183Thrfs*5) has been determined to be pathogenic (PMID: 16311595, 19370762, 23954310). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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