ClinVar Miner

Submissions for variant NM_172250.3(MMAA):c.593_596del (p.Thr198fs) (rs796051993)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186013 SCV000238975 pathogenic not provided 2014-08-18 criteria provided, single submitter clinical testing The c.593_596delCTGA deletion causes a frameshift starting with codon Threonine 198, changes this amino acid to a Serine residue and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Thr198SerfsX6. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. c.593_596delCTGA has been reported previously in association with methylmalonic acidemia (MMA) (Lerner-Ellis et al., 2004; aka c.592_595delACTC). The variant is found in MMAA panel(s).
GeneReviews RCV000203312 SCV000258483 pathogenic Methylmalonic aciduria cblA type 2016-01-07 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000780425 SCV000917669 pathogenic Methylmalonic acidemia 2018-03-19 criteria provided, single submitter clinical testing Variant summary: MMAA c.593_596delCTGA (p.Thr198SerfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.7e-05 in 246266 control chromosomes. This frequency is not higher than expected for a pathogenic variant in MMAA causing Methylmalonic Acidemia (3.7e-05 vs 0.0018), allowing no conclusion about variant significance. The c.593_596delCTGA variant has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia, both as a homozygous and compound heterozygous allele. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, with the most pronounced variant effect resulting in 10%-<30% of normal activity (Lerner-Ellis_2004). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000780425 SCV000967584 pathogenic Methylmalonic acidemia 2018-12-03 criteria provided, single submitter clinical testing The p.Thr198SerfsX6 variant in MMAA has been reported in at least 5 compound het erozygous and 1 homozygous individuals with methylmalonic acidemia (Lerner-Ellis , 2004). It has also been identified in 10/129132 of European chromosomes by gno mAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a fra meshift, which alters the protein?s amino acid sequence beginning at position 19 8 and leads to a premature termination codon 6 amino acids downstream. This alte ration is then predicted to lead to a truncated or absent protein. Loss of funct ion of the MMAA gene is an established disease mechanism in autosomal recessive methylmalonic acidemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive methylmalonic acidemia. ACMG/AMP Criteria applied: PM2_Supportive, PVS1, PM3_Very Strong.
OMIM RCV000203312 SCV000023464 pathogenic Methylmalonic aciduria cblA type 2002-11-26 no assertion criteria provided literature only

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