ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.1106G>A (p.Arg369His) (rs564069299)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000203318 SCV000796991 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-01-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000203318 SCV000893722 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000186046 SCV000239010 pathogenic not provided 2017-03-21 criteria provided, single submitter clinical testing The R369H missense change in the MUT gene has been reported previously in association with methylmalonic acidemia (Janata et al. 1997; Lempp et al. 2007; Han et al. 2015). Expression studies found that R369H is associated with 1.3% methylmalonyl-CoA mutase activity compared to wild type (Forny et al. 2014). The R369H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we interpret R369H to be a pathogenic variant.
GeneReviews RCV000203318 SCV000258503 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2016-01-07 no assertion criteria provided literature only
Invitae RCV000203318 SCV000641771 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-10-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 369 of the MUT protein (p.Arg369His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. The frequency data for this variant (rs564069299) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been reported in the literature in multiple individuals affected with methylmalonic acidemia as homozygous or in combination with other MUT variants  (PMID: 27751223, 16281286, 17075691, 27167370, 9929975, 16490061, 17113806, 22614770). ClinVar contains an entry for this variant (Variation ID: 203846). Experimental studies have shown that this missense change causes a profound reduction on MUT enzyme activity (PMID: 25125334). For these reasons, this variant has been classified as Pathogenic.

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