ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.181C>T (p.Arg61Trp)

gnomAD frequency: 0.00072  dbSNP: rs200483477
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186023 SCV000238985 uncertain significance not provided 2023-03-23 criteria provided, single submitter clinical testing Reported as homozygous in a patient with cobalamin C deficiency who was also homozygous for R111X (Lerner-Ellis et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16311595, 28337550, 19370762, 32439973)
Invitae RCV000552129 SCV000640283 uncertain significance Cobalamin C disease 2022-09-19 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 61 of the MMACHC protein (p.Arg61Trp). This variant is present in population databases (rs200483477, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with cobalamin C deficiency (PMID: 16311595, 19370762). ClinVar contains an entry for this variant (Variation ID: 203824). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MMACHC protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina RCV001099137 SCV001255560 uncertain significance Disorders of Intracellular Cobalamin Metabolism 2017-05-22 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Elsea Laboratory, Baylor College of Medicine RCV000552129 SCV001424219 uncertain significance Cobalamin C disease 2020-04-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000552129 SCV001805874 uncertain significance Cobalamin C disease 2021-07-14 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000186023 SCV002062805 uncertain significance not provided 2021-11-01 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000552129 SCV002581507 uncertain significance Cobalamin C disease 2021-08-20 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000552129 SCV002790524 uncertain significance Cobalamin C disease 2022-04-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV002517826 SCV003634758 uncertain significance Inborn genetic diseases 2022-04-14 criteria provided, single submitter clinical testing The c.181C>T (p.R61W) alteration is located in exon 2 (coding exon 2) of the MMACHC gene. This alteration results from a C to T substitution at nucleotide position 181, causing the arginine (R) at amino acid position 61 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV003458351 SCV004183524 uncertain significance Methylmalonic aciduria, type cblc 2023-11-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000186023 SCV004227832 uncertain significance not provided 2023-06-09 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000552129 SCV000986768 not provided Cobalamin C disease no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 12/09/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc. RCV001277240 SCV001464147 uncertain significance Methylmalonic acidemia with homocystinuria cblC 2019-08-02 no assertion criteria provided clinical testing

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