ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Invitae RCV000203318 SCV000641771 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2019-10-04 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.
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
CeGaT Praxis fuer Humangenetik Tuebingen RCV000186046 SCV001246219 pathogenic not provided 2019-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192655 SCV001360914 pathogenic Methylmalonic acidemia 2019-03-29 criteria provided, single submitter clinical testing Variant summary: MUT c.1106G>A (p.Arg369His) results in a non-conservative amino acid change located in the Methylmalonyl-CoA mutase, alpha/beta chain, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.2e-05 in 276352 control chromosomes (gnomAD). The variant, c.1106G>A, has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Mikami_1999, Sakamoto_2007, Harrington_2016). These data indicate that the variant is very likely to be associated with disease. In vitro studies indicate that this variant is associated with 1.3% of MUT activity compared to WT (Forny_2014). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic
GeneReviews RCV000203318 SCV000258503 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2016-01-07 no assertion criteria provided literature only

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