Patient Report |FINAL

Client: Example Client ABC123 Patient: Patient, Example 123 Test Drive Salt Lake City, UT 84108 DOB 12/1/2019 UNITED STATES Gender: Male Patient Identifiers: 01234567890ABCD, 012345 Physician: Doctor, Example Visit Number (FIN): 01234567890ABCD Collection Date: 01/01/2017 12:34

Medium Chain Acyl-CoA Dehydrogenase Deficiency (ACADM) Sequencing ARUP test code 0051758 MCAD FGS Specimen Whole Blood

MCAD Deficiency (ACADM) Sequencing Positive * TEST PERFORMED - 0051758 TEST DESCRIPTION - Medium Chain Acyl-CoA Dehydrogenase Deficiency (ACADM) Sequencing INDICATION FOR TEST - Confirm Diagnosis

RESULT Two apparent copies of a pathogenic variant were detected in the ACADM gene.

DNA VARIANT Classification: Pathogenic Gene: ACADM Nucleic Acid Change: c.985A>G; Homozygous Amino Acid Alteration: p.Lys329Glu

INTERPRETATION Two apparent copies of a pathogenic variant, c.985A>G; p.Lys329Glu, were identified in the ACADM gene by sequencing. This result is consistent with a diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.

Evidence for variant classification: 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.

RECOMMENDATIONS Genetic and dietary consultations are strongly recommended. Parental testing for the identified variant is recommended to confirm that two copies of the pathogenic variant are present, and family members should be offered targeted sequencing for the identified pathogenic variants (Familial Mutation, Targeted Sequencing, ARUP test code 2001961). This individual's future reproductive partner should be offered carrier testing for MCAD deficiency.

H=High, L=Low, *=Abnormal, C=Critical

Patient: Patient, Example ARUP Accession: 19-339-402672 Patient Identifiers: 01234567890ABCD, 012345 Visit Number (FIN): 01234567890ABCD Page 1 of 3 | Printed: 1/28/2021 2:35:08 PM 4848 Patient Report |FINAL

COMMENTS Reference Sequence: GenBank # NM_000016.4 (ACADM) Nucleotide numbering begins at the "A" of the ATG initiation codon. Likely benign and benign variants are not reported.

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.

This result has been reviewed and approved by

BACKGROUND INFORMATION: Medium Chain Acyl-CoA Dehydrogenase Deficiency (ACADM) Sequencing CHARACTERISTICS: Limited mitochondrial fatty acid beta-oxidation leading to hypoglycemia, lethargy, seizures, hypoketotic dicarboxylic aciduria, vomiting, hepatomegaly, hepatic failure, encephalopathy, and sudden death. Manifestations often triggered by prolonged fasting or other metabolic stressors. INCIDENCE: 1 in 15,000. INHERITANCE: Autosomal recessive. CAUSE: Deleterious ACADM gene mutations. CLINICAL SENSITIVITY: 95 to 99 percent. METHODOLOGY: Polymerase chain reaction (PCR) followed by bidirectional sequencing of the entire coding region and intron/exon boundaries of the ACADM gene. ANALYTICAL SPECIFICITY AND SENSITIVITY: 99 percent. LIMITATIONS: Diagnostic errors can occur due to rare sequence variations. Regulatory region mutations, deep intronic mutations, and large deletion/ duplications will not be detected. Test developed and characteristics determined by ARUP Laboratories. See Compliance Statement C: aruplab.com/CS

H=High, L=Low, *=Abnormal, C=Critical

Patient: Patient, Example ARUP Accession: 19-339-402672 Patient Identifiers: 01234567890ABCD, 012345 Visit Number (FIN): 01234567890ABCD Page 2 of 3 | Printed: 1/28/2021 2:35:08 PM 4848 Patient Report |FINAL

VERIFIED/REPORTED DATES

Procedure Accession Collected Received Verified/Reported

MCAD FGS Specimen 19-339-402672 12/5/2019 1 27:00 PM 12/5/2019 6:14:09 PM 12/18/2019 3:48 00 PM

MCAD Deficiency (ACADM) Sequencing 19-339-402672 12/5/2019 1 27:00 PM 12/5/2019 6:14:09 PM 12/18/2019 3:48 00 PM

END OF CHART

H=High, L=Low, *=Abnormal, C=Critical

Patient: Patient, Example ARUP Accession: 19-339-402672 Patient Identifiers: 01234567890ABCD, 012345 Visit Number (FIN): 01234567890ABCD Page 3 of 3 | Printed: 1/28/2021 2:35:08 PM 4848