ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.655A>T (p.Asn219Tyr) (rs121918256)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186055 SCV000239019 pathogenic not provided 2018-12-24 criteria provided, single submitter clinical testing The N219Y mutation [p.Asn219Tyr (AAT>TAT): c.655 A>T in exon 3 of the MUT gene (NM_000255.3)] is a missense mutation was identified on 8 of 10 alleles in patients with methylmalonic acidemia of French and Turkish decent (Acquaviva et al., 2001). Expression studies found that N219Y abolishes methylmalonyl-CoA mutase activity, and patients homozygous for the N219Y mutation have the severe mut 0 phenotype (Acquaviva et al., 2001). N219Y was found at a 1% carrier frequency in a French control population (Acquaviva et al., 2001). The variant is found in MMA-MET panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587363 SCV000696308 pathogenic Methylmalonic acidemia 2017-04-13 criteria provided, single submitter clinical testing Variant summary: The MUT c.655A>T (p.Asn219Tyr) variant involves the alteration of a conserved nucleotide, which is located in Cobalamin (vitamin B12)-dependent enzyme, catalytic domain. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 7/120870 control chromosomes at a frequency of 0.0000579, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUT variant (0.0024152). This variant has been found multiple patients with MUT-related methylmalonic acidemia. Enzyme activity in the patients who carry homozygous p.N219Y was extremely low compared to normal values (Lempp_2007), suggesting p.N219Y is damaging to MUT normal function. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Counsyl RCV000203309 SCV000789641 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-02-08 criteria provided, single submitter clinical testing
Invitae RCV000186055 SCV001377093 pathogenic not provided 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces asparagine with tyrosine at codon 219 of the MUT protein (p.Asn219Tyr). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and tyrosine. This variant is present in population databases (rs121918256, ExAC 0.01%). This variant has been reported as homozygous or in combination with another MUT variant in individuals affected with methylmalonic acidemia (PMID: 11528502, 17957493, 24059531). ClinVar contains an entry for this variant (Variation ID: 1886). Experimental studies have shown that this missense change abrogates MUT enzyme activity (PMID: 11528502). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000001963 SCV000022121 pathogenic METHYLMALONIC ACIDURIA, mut(0) TYPE 2005-02-01 no assertion criteria provided literature only
GeneReviews RCV000203309 SCV000258500 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2016-01-07 no assertion criteria provided literature only
Institute of Medical Genetics and Genomics,Sir Ganga Ram Hospital RCV000203309 SCV000267123 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2012-06-15 no assertion criteria provided research
Natera, Inc. RCV001271716 SCV001453064 pathogenic Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency 2020-09-16 no assertion criteria provided clinical testing

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