ClinVar Miner

Submissions for variant NM_172250.3(MMAA):c.433C>T (p.Arg145Ter) (rs104893851)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000003310 SCV000486597 pathogenic Methylmalonic aciduria cblA type 2016-11-03 criteria provided, single submitter clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000003310 SCV000238443 pathogenic Methylmalonic aciduria cblA type 2015-01-08 no assertion criteria provided research The heterozygous variant in the MMAA gene (c.433C>T; p.Arg145*) is considered a pathogenic variant. This change represents a rare premature truncation resulting in a product 1/3 of the expected length with the last ~ 273 amino acids being truncated off. This variant has been seen previously by Yang et al (PMID: 15308131) in a one individual in a Japanese affected individuals. In the ExAC dataset this variant was seen on 19 alleles out of 121038 tested, with all tested individuals being heterozygous for the change.
Foundation for Research in Genetics and Endocrinology,Institute of Human Genetics RCV000003310 SCV000882545 pathogenic Methylmalonic aciduria cblA type 2018-12-18 no assertion criteria provided clinical testing The variant NM_172250.3:c.433C>T (p.Arg145Ter) in exon-2 of MMAA gene has been seen in heterozygous status. It is a nonsense variant that results in a stop codon and premature truncation of the protein. This variant has not been reported in the 1000 Genomes database and has a minor allele frequency of 0.02% in the ExAc database. The in-silico prediction of this variant is damaging by MutationTaster2.
GeneDx RCV000186012 SCV000238974 pathogenic not provided 2018-10-08 criteria provided, single submitter clinical testing The R145X nonsense variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. R145X has been reported previously in association with methylmalonic acidemia (MMA) (Lerner-Ellis et al., 2004; Yang et al., 2004).
GeneReviews RCV000003310 SCV000258475 pathogenic Methylmalonic aciduria cblA type 2016-12-01 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000587855 SCV000699975 pathogenic Methylmalonic acidemia 2016-02-17 criteria provided, single submitter clinical testing Variant summary: MMAA c.433C>T variant results in a premature termination at codon 145 (274 amino acids from the end of the protein), predicted to cause a truncated or absent MMAA protein, which is a commonly known mechanism for methylmalonic academia. Mutation Taster predicts a damaging outcome for this variant; this predictions is supported by functional studies showing that patients homozygous for R145X have a "reduced ability to incorporate propionate into cellular macromolecules, an indirect measure of AdoCbl-dependent MCM activity" (10-29% of WT activity). This variant is found in 19/119564 control chromosomes at a frequency of 0.0001589, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0018257). The variant of interest has been reported in many patients from the literature, and R145X is a common disease variant that has been reported to represent 45% of pathogenic MMAA alleles (Lerner-Ellis et al. 2004). In addition, several clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this is a disease variant and was classified as pathogenic.
Invitae RCV000003310 SCV000641766 pathogenic Methylmalonic aciduria cblA type 2019-01-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg145*) in the MMAA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs104893851, ExAC 0.04%). This variant has been reported as homozygous or in combination with another MMAA variant in several individuals affected with methylmalonic aciduria due to cobalamin A deficiency (PMID: 15308131, 17957493, 16247646, 15523652, 27591164, 26270765, 23026888). Loss-of-function variants in MMAA are known to be pathogenic (PMID: 15523652, 15781192). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000587855 SCV000713163 pathogenic Methylmalonic acidemia 2017-05-01 criteria provided, single submitter clinical testing The p.Arg145X (NM_172250.2 c.433C>T) variant in MMAA has been reported in 2 het erozygous, 12 homozygous (2 of which were consanguineous) and 10 compound hetero zygous individuals with methylmalonic acidemia (Lerner-Ellis 2004, Yang 2004, Ha armann 2013, and Devi 2017). This variant has also been reported in ClinVar (Var iation ID#3160) as pathogenic by multiple laboratories. This variant has been id entified in 0.04% (6/16350) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs104893851). Although t his variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant lead s to a premature termination codon at position 145, which is predicted to lead t o a truncated or absent protein. Biallelic loss of function of the MMAA gene has been associated with methylmalonic acidemia. In summary, this variant meets cr iteria to be classified as pathogenic for methylmalonic acidemia in an autosomal recessive manner based upon its biallelic occurrence in individuals with this d isease and predicted null effect on the protein.
OMIM RCV000003310 SCV000023468 pathogenic Methylmalonic aciduria cblA type 2004-12-01 no assertion criteria provided literature only

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