ClinVar Miner

Submissions for variant NM_000016.6(ACADM):c.199T>C (p.Tyr67His) (rs121434280)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000003780 SCV000056311 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2015-02-20 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000185668 SCV000077249 pathogenic not provided 2017-01-24 criteria provided, single submitter clinical testing
GeneDx RCV000185668 SCV000238587 pathogenic not provided 2018-09-06 criteria provided, single submitter clinical testing The Y67H variant in the ACADM gene has been identified on approximately 7% of alleles inindividuals with a positive newborn screen result for medium chain acyl-CoA dehydrogenase (MCAD)deficiency (Maier et al., 2005; Andresen et al., 2001). Clinical studies of individuals identified bynewborn screening and in vitro experiments show that Y67H is a mild folding variant, associated witha milder biochemical phenotype. However there is not a consistent relationship between specificgenotypes and the development of clinical symptoms in MCAD deficiency. Individuals harboring theY67H variant and a second pathogenic ACADM variant are still considered to be at risk fordeveloping clinical manifestations.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000185668 SCV000600032 pathogenic not provided 2016-11-10 criteria provided, single submitter clinical testing
Invitae RCV000003780 SCV000630280 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 67 of the ACADM protein (p.Tyr67His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs121434280, ExAC 0.1%). This variant is known as a prevalent ACADM mutation identified in individuals positive for newborn screening (PMID: 15479234). This variant has mostly been found in individuals with biochemically confirmed MCAD deficiency as compound heterozygous with the pathogenic variant c.985A>G (p.Lys329Glu) (PMID: 16291504, 22166308, 18188679, 20434380, 20036593). It has also been observed as compound heterozygous with other severe ACADM mutations in individuals affected with neonatal decompensation with hypoglycemia (PMID: 22848008, 25940036). This variant is also known as p.Y42H in the literature. ClinVar contains an entry for this variant (Variation ID: 3597). Experimental studies have consistently shown that this variant results in a temperature-sensitive enzyme with partial activity (PMID: 15479234, 19224950, 24718418). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000185668 SCV000692632 pathogenic not provided 2020-06-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000003780 SCV000693956 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2016-12-15 criteria provided, single submitter clinical testing Variant summary: The ACADM c.199T>C (p.Tyr67His) variant located in the Acyl-CoA dehydrogenase/oxidase, N-terminal and middle domain causes a missense change involving a conserved nucleotide that 3/4 in silico tools (SNPs&GO not captured here due to low reliability) predict a benign outcome. The variant of interest was observed in controls with an allele frequency of 74/121100 (1/1636), which does not exceed the estimated maximal expected allele frequency for a pathogenic ACADM variant of 1/184. The variant of interest has been reported in multiple affected individuals as compound heterozygous, which have been implicated to have mild phenotypes, to the point where multiple authors indicate individuals with this variant do not present clinically. In addition, multiple functional studies have been performed and show the variant has a mild affect on wild type functionality. In addition, multiple clinical diagnostic laboratories/databases cite variant as "pathogenic." Therefore, taking all available information into consideration, the variant of interest has been classified as "pathogenic" for a mild MCAD phenotype.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000003780 SCV000711420 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2017-03-31 criteria provided, single submitter clinical testing The p.Tyr71His variant in ACADM (NM_001127328.1 c.211T>C; also referred to as c. 199Y>C, T42H, and T67H) has been reported in > 15 compound heterozygous individu als with mild medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (Zschocke 20 01, Touw 2013, and Gramer 2015), and segregated in 1 sibling in 1 family (Touw 2 013). This variant has also been reported in ClinVar (Variation ID#3597). This v ariant has been identified in 0.10% (69/66,614) of European chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs12143 4280). Although this variant has been seen in the general population, its freque ncy is low enough to be consistent with a recessive carrier frequency, particula rly with one presenting with a mild phenotype. In vitro functional studies provi de some evidence that the p.Tyr71 variant may modestly impact protein function ( O'Reilly 2004, Maier 2009, Koster 2014, Jank 2014, and Hara 2016). However, thes e assays show a decreased, but not eliminated, residual activity. It is unclear how this mild biochemical reduction may lead to a clinical phenotype. In summary , although additional studies are required to fully establish its clinical signi ficance, the p.Tyr71His variant is likely pathogenic in an autosomal recessive m anner for mild MCAD deficiency.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000185668 SCV000884947 pathogenic not provided 2018-04-05 criteria provided, single submitter clinical testing The ACADM c.199T>C; p.Tyr67His variant (rs121434280), also known as Y42H, was identified through newborn screening and results in an abnormal acylcarnitine profile when paired with a second ACADM pathogenic variant on the opposite allele (Maier 2009, O'Reilly 2004, Zschocke 2001). It is reported as pathogenic by several laboratories in ClinVar (Variation ID: 3597) and is observed in the general population at an overall frequency of 0.05% (135/277162 alleles) in the Genome Aggregation Database. Functional analyses demonstrate that this variant results in a temperature-sensitive enzyme with partial activity (Jank 2014, Maier 2009, O'Reilly 2004). Based on available information, this variant is considered pathogenic. References: Jank J et al. The domain-specific and temperature-dependent protein misfolding phenotype of variant medium-chain acyl-CoA dehydrogenase. PLoS One. 2014 Apr 9;9(4):e93852. Maier EM et al. Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screening. Hum. Mol. Genet. 2009; 18(9):1612-23. O'Reilly L et al. The Y42H mutation in medium-chain acyl-CoA dehydrogenase, which is prevalent in babies identified by MS/MS-based newborn screening, is temperature sensitive. Eur. J. Biochem. 2004; 271(20):4053-63. Zschocke J et al. Molecular and functional characterisation of mild MCAD deficiency. Hum. Genet. 2001; 108(5):404-8.
Myriad Women's Health, Inc. RCV000003780 SCV001193986 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2019-12-20 criteria provided, single submitter clinical testing NM_000016.4(ACADM):c.199T>C(Y67H) is classified as pathogenic in the context of medium chain acyl-CoA dehydrogenase deficiency and is associated with a mild form of this disease. Sources cited for classification include the following: PMIDs: 15832312, 20434380, 11409868, 19224950, 23028790, 23509891, and 24718418. Classification of NM_000016.4(ACADM):c.199T>C(Y67H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000003780 SCV001251466 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency criteria provided, single submitter research The ACADM c.199T>C (p.Y67H) missense variant has been previously reported as pathogenic for medium-chain acyl-coA dehydrogenase deficiency in compound heterozygous individuals with a second, more severe ACADM variant. This variant is also referred to as Y42H (PMID: 11409868; 25940036; 11349232).
OMIM RCV000003780 SCV000023945 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2008-03-01 no assertion criteria provided literature only

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