ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.328_331del (p.Asn110fs) (rs796052000)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186035 SCV000238999 pathogenic not provided 2017-11-13 criteria provided, single submitter clinical testing The c.328_331delAACC variant in the MMACHC gene has been reported previously in association with methylmalonic aciduria and homocystinuria, cblC type (cblC disease) (Lerner-Ellis et al., 2006; Weisfeld-Adams et al., 2013). This deletion causes a frameshift starting with codon Asparagine 110, changes this amino acid to an Aspartic Acid residue and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Asn110AspfsX13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This finding is consistent with a diagnosis of methylmalonic aciduria and homocystinuria, cblC type in this patient. However, this result could also be seen if the patient had one allele with the c.328_331delAACC pathogenic variant and one allele that was partially missing or refractory to amplification.
Integrated Genetics/Laboratory Corporation of America RCV000531346 SCV000699396 pathogenic Methylmalonic acidemia with homocystinuria 2016-04-12 criteria provided, single submitter clinical testing Variant summary: The c.328_331delAACC variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein, which is a commonly known mechanism for disease. Truncations downstream of this position have also been associated with CBLC phenotype (e.g. p.Arg132X). One in-silico tool predicts damaging outcome for this variant. This variant is not found in approximately120716 control chromosomes from the large and broad populations of ExAC. This variant has been reported in several patients with CBLC. Multiple reputable databases and one clinical lab has classified this variant as pathogenic. Taken together, this variant has been classified as a Disease Variant/Pathogenic.
Invitae RCV000531346 SCV000640287 pathogenic Methylmalonic acidemia with homocystinuria 2018-10-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn110Aspfs*13) in the MMACHC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs777767443, ExAC 0.03%). This variant has been reported as homozygous or in combination with another MMACHC variant in individuals affected with methylmalonic aciduria and homocystinuria, cobalamin C (cblC) type (PMID: 16311595, 19370762, 23954310, 24126030). ClinVar contains an entry for this variant (Variation ID: 203835). 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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