ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.848G>C (p.Ter283Ser) (rs201025783)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669635 SCV000794408 uncertain significance Methylmalonic acidemia with homocystinuria 2017-09-26 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000729719 SCV000857405 uncertain significance not provided 2018-01-25 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000669635 SCV000896410 uncertain significance Methylmalonic acidemia with homocystinuria 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780428 SCV000917674 uncertain significance not specified 2018-12-10 criteria provided, single submitter clinical testing Variant summary: MMACHC c.848G>C (p.X283SerextX14) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. The variant allele was found at a frequency of 0.00026 in 276092 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in MMACHC causing Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria) (0.00026 vs 0.0031), allowing no conclusion about variant significance. Another variant affecting the same nucleotide and leading to a different, though functionally similar protein level change, MMACHC c.848G>T (p.Ter283LeuextTer14) is reported in 275/276092 gnomAD alleles, almost exclusively observed within the Latino subpopulation with 274/34392 alleles (frequency: 0.008), including 4 homozygotes. This frequency is higher than the MPAF (0.0031), suggesting that the loss of STOP codon leading to a 14 amino acid extension of the protein might not be detrimental for protein function. c.848G>C has been reported in the literature (Abuli 2016). This report however does not provide unequivocal conclusions about association of the variant with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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