ClinVar Miner

Submissions for variant NM_052845.4(MMAB):c.584G>A (p.Arg195His) (rs756195708)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000780426 SCV000917670 likely pathogenic Methylmalonic acidemia 2018-04-16 criteria provided, single submitter clinical testing Variant summary: MMAB c.584G>A (p.Arg195His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Five predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Jorge-Finnigan_2010). The variant was observed with an allele frequency of 8.2e-06 in 243566 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MMAB causing Methylmalonic Acidemia (8.2e-06 vs 0.0014), allowing no conclusion about variant significance. The variant, c.584G>A, was observed in two siblings, one presenting with Methylmalonic Acidemia, while the sibling with the same genotype was asymptomatic (Jorge-Finnigan_2010). Multiple publications have functionally assessed the variant and observed the variant to affect splicing, but does produce a limited amount of wild type protein (Jorge-Finnigan_2010), along with presenting functional implications on proper MMAB protein function (Brasil_2015). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM RCV000202574 SCV000257518 pathogenic Methylmalonic aciduria cblB type 2010-09-01 no assertion criteria provided literature only

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