ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.316G>A (p.Glu106Lys) (rs201617713)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000415822 SCV000238987 uncertain significance not provided 2018-05-22 criteria provided, single submitter clinical testing The E106K variant in the MMACHC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E106K variant is observed in 140/277090 (0.051%) alleles in large population cohorts, with no homozygotes observed (Lek et al., 2016). The E106K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret E106K as a variant of uncertain significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000415822 SCV000493221 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing
Invitae RCV000552788 SCV000640286 uncertain significance Cobalamin C disease 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 106 of the MMACHC protein (p.Glu106Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs201617713, ExAC 0.06%) but has not been reported in the literature in individuals with a MMACHC-related disease. ClinVar contains an entry for this variant (Variation ID: 203826). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Therefore, it has been classified as a Variant of Uncertain Significance.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000552788 SCV000923541 uncertain significance Cobalamin C disease 2019-01-01 criteria provided, single submitter clinical testing
Mendelics RCV000552788 SCV001135277 uncertain significance Cobalamin C disease 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001099138 SCV001255561 uncertain significance Disorders of Intracellular Cobalamin Metabolism 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Natera, Inc. RCV001273218 SCV001456010 uncertain significance Methylmalonic acidemia with homocystinuria cblC 2020-09-16 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000415822 SCV001741200 uncertain significance not provided no assertion criteria provided clinical testing

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