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

Total submissions: 7

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