ClinVar Miner

Submissions for variant NM_000016.6(ACADM):c.985A>G (p.Lys329Glu) (rs77931234)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000003769 SCV000056310 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2015-02-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000003769 SCV000196972 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2014-11-07 criteria provided, single submitter clinical testing The p.Lys333Glu variant (NM_001127328.1 c.997A>G) in ACADM is the most prevalent pathogenic variant for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency an d has been reported in over 100 individuals with this disease (Matsubara 1990, A ndersen 2001, Strum 2012). This variant has been reported in ClinVar (Variation# 3586) as pathogenic. While this variant has been identified in 0.6% (778/126684) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs77931234), its frequency is low enough to be cons istent with a recessive carrier frequency. This variant has been demonstrated to lead to reduced enzyme activity in carrier individuals and in vitro studies pro vide evidence that it impacts protein function (Strum 2012); however, these type s of assays may not accurately represent biological function. In summary, this v ariant meets criteria to be classified as pathogenic for MCAD deficiency in an a utosomal recessive manner.
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000003769 SCV000236527 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2014-11-06 criteria provided, single submitter clinical testing
GeneDx RCV000077895 SCV000238584 pathogenic not provided 2018-10-15 criteria provided, single submitter clinical testing K329E is the most common pathogenic variant in the ACADM gene and accounts for approximately 67% of mutant ACADM alleles (Matern, D. and Rinaldo, P. 2015). We interpret K329E as a pathogenic variant.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000077895 SCV000280721 pathogenic not provided 2015-03-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000003769 SCV000358942 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2017-09-29 criteria provided, single submitter clinical testing The ACADM c.985A>G (p.Lys329Glu) missense variant is widely reported as the most common pathogenic variant in the Caucasian population accounting for approximately 67% of disease alleles for MCAD deficiency (Matern et al. 2000). Across a selection of the available literature, the p.Lys329Glu variant has been identified in over 168 MCAD deficiency patients including 103 in a homozygous state, 54 in a compound heterozygous state, and 11 in a heterozygous state (Matsubara et al. 1990; Andresen et al. 2001; Maier et al. 2005; Sturm et al. 2012; Fernández-Guerra et al. 2014). The variant was absent from 29 controls and is reported at a frequency of 0.00744 in the European American population of the Exome Sequencing Project. Functional studies have demonstrated that the variant results in significantly reduced enzyme activity compared to wild type of less than 10% in homozygotes and 12% in compound heterozygotes, which is significantly below the 20-30% threshold associated with disease phenotypic presentation (Sturm et al. 2012). The variant is reported to cause protein misfolding (Fernández-Guerra et al. 2014). Based on the collective evidence, the p.Lys329Glu variant is classified as pathogenic for medium-chain acyl-CoA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000003769 SCV000538011 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2015-09-26 criteria provided, single submitter clinical testing The c.985A>G, p.Lys329Glu variant (position is based on the precursor protein) variant has been observed in the homozygous state in several individuals who were diagnosed with MCAD deficiency (Matsubara, Y et al., 1990; Yokota et al., 1991). The prevalence of this variant in affected individuals is significantly increased compared with the prevalence in controls. Biochemically, this variant is in a domain that is critical for enzymatic activity and in vitro functional studies have demonstrated that the p.Lys329Glu variant results in protein misfolding, increased hydrophobicity and altered enzyme kinetics (Jank et al., 2014; Maier et al., 2009). The frequency of the variant in the population databases (Exome Sequencing Project and ExAC) is lower than the world-wide disease allele frequency. Finally, reputable sources have classified this variant as Pathogenic. In summary, this variant meets our criteria for a Pathogenic classification. We have confirmed this finding in our laboratory using Sanger sequencing.
Invitae RCV000003769 SCV000630299 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2020-01-06 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 329 of the ACADM protein (p.Lys329Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs77931234, ExAC 0.5%). This variant is a known prevalent ACADM mutation (PMID: 16763904, 23574375, 2393404, 7904584). It has been reported in many symptomatic individuals affected with MCAD deficiency as homozygous or in combination with other ACADM variants (PMID: 16737882, 15832312, 16291504, 16617240, 16763904, 23574375). This variant is also known as p.Lys304Glu or K304E in the literature. ClinVar contains an entry for this variant (Variation ID: 3586). Experimental studies have shown that this variant causes a loss of enzymatic activity measured in lymphocytes from patients who are homozygous for this variant (PMID: 23028790, 22630369). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000003769 SCV000693963 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2016-06-10 criteria provided, single submitter clinical testing Variant summary: The ACADM c.985A>G (p.Lys329Glu) variant involves the alteration of a conserved nucleotide. 1/4 in silico tools predict a damaging outcome. This variant was found in 402/121176 control chromosomes (including 1 homozygote) at a frequency of 0.0033175, which does not exceed the estimated maximal expected allele frequency of a pathogenic ACADM variant (0.0036228). The variant is the most common mutation causing MCAD. The variant is widely reported in literature with consistent genotype and functional assays show that it leads to defective enzymatic activity. Several clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000003769 SCV000782448 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2016-05-03 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000077895 SCV000883328 pathogenic not provided 2017-05-19 criteria provided, single submitter clinical testing The ACADM c.985A>G; p.Lys329Glu variant (rs77931234) is the most common pathogenic variant associated with MCAD deficiency (Andresen 2001, Sturm 2012, Yokota 1990). Functional characterization of fibroblasts from homozygous individuals show reduced residual enzymatic activity (Sturm 2012), with the variant protein below the detection level in Western Blot analysis (Yokota 1990). The variant is listed as pathogenic in ClinVar (Variation ID: 3586), and observed in the general population in 0.33% (911/277174 alleles, including 1 homozygote) in the Genome Aggregation. Based on the above information, the p.Lys329Glu variant is classified as pathogenic. References: Andresen B et al. Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency. Am J Hum Genet. 2001; 68(6):1408-18. Sturm M et al. Functional effects of different medium-chain acyl-CoA dehydrogenase genotypes and identification of asymptomatic variants. PLoS One. 2012 7(9):e45110. Yokota I et al. Molecular basis of medium chain acyl-coenzyme A dehydrogenase deficiency. An A to G transition at position 985 that causes a lysine-304 to glutamate substitution in the mature protein is the single prevalent mutation. J Clin Invest. 1990; 86(3):1000-3.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077895 SCV000887498 pathogenic not provided 2015-09-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000003769 SCV000894144 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2018-10-31 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000003769 SCV000930256 uncertain significance Medium-chain acyl-coenzyme A dehydrogenase deficiency 2019-04-27 criteria provided, single submitter clinical testing
Mendelics RCV000003769 SCV001135310 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2019-05-28 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000003769 SCV001149660 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2018-10-30 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000003769 SCV001194073 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2019-10-18 criteria provided, single submitter clinical testing NM_000016.4(ACADM):c.985A>G(K329E, aka K304E) is classified as pathogenic in the context of medium chain acyl-CoA dehydrogenase deficiency. Sources cited for classification include the following: PMID 16763904, 23028790, 19224950, 15832312, 20434380, 23509891, 16291504, 18241067. Classification of NM_000016.4(ACADM):c.985A>G(K329E, aka K304E) 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000077895 SCV001245626 pathogenic not provided 2020-06-01 criteria provided, single submitter clinical testing
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000003769 SCV001251448 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency criteria provided, single submitter research The ACADM c.985A>G (p.K329E) missense variant has been reported as one of the most commonly observed pathogenic variants in individuals with medium-chain acyl-coA dehydrogenase deficiency (PMID: 1684086;1902818; 11349232).
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001195788 SCV001366208 likely pathogenic Hypothyroidism; Decreased body weight; Severe intrauterine growth retardation; Severe postnatal growth retardation; Congenital microcephaly 2020-02-03 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3,BS2. This variant was detected in heterozygous state.
OMIM RCV000003769 SCV000023934 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2014-03-01 no assertion criteria provided literature only
Baylor Genetics RCV000003769 SCV000328760 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2016-02-11 no assertion criteria provided clinical testing Our laboratory reported dual molecular diagnoses in GNAO1 (NM_138736.2, c.692A>G) and ACADM (NM_000016.4, c.287-2A>G and c.985A>G in trans) in one individual with reported features of medium chain acyl-CoA dehydrogenase deficiency, history of prematurity, developmental regression and seizures, non-ocular blindness. The c.985A>G (p.K329E) ACADM variant has been reported as a common disease causing variant [also referred to as K304E; PMID 8104486, 7652482]. Heterozygotes would be expected to be asymptomatic carriers.
GenomeConnect, ClinGen RCV000003769 SCV000840097 not provided Medium-chain acyl-coenzyme A dehydrogenase deficiency no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Reproductive Health Research and Development,BGI Genomics RCV000003769 SCV001142300 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2020-01-06 no assertion criteria provided curation NM_000016.4:c.985A>G in the ABCA4 gene has an allele frequency of 0.006 in European(non-Finnish) subpopulation in the gnomAD database. Sturm M et al found that 21 subjects with suspected MCAD deficiency were characterized as homozygous for the prevalent mutation c.985A>G and 4 were compound heterozygotes containing one copy of the prevalent mutation c.985A>G together with known or novel missense mutations, small deletions, or insertions and had residual activities between 0-12% (PMID: 23028790). Experimental studies have shown that c.985A>G causes a loss of enzymatic activity measured in lymphocytes from patients who are homozygous for this variant (PMID: 23028790; 22630369). The patient's phenotype is highly specific for ABCA4 gene(PMID: 16737882). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationTaster, PrimateAI and REVEL. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PM3_Strong; PS3; PP3; PP4.

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