Monoallelic, AD

Case#: Muriello case

CaseHPOs: HP:0003235 (hypermethioninemia)

CaseHPOsFreeText: Elevated methionine on newborn screen. Intermottent elevations of ALT (66 and 88 U/L) with normal AST, alkaline phosphatase and total bilirubin.

CaseNotHPOsFreeText: Normal plasma homocysteine

CasePreviousTesting: Plasma methionine 0.81 mg/dL (54 μmol/L) at 1 day, 1.08 mg/dL (73 μmol/L) at 16 days (normal < 0.8 mg/dL). Methionine concentration was 175, 185, 192, 136, 75 μmol/L (reference range 9–43 μmol/L) at ages 3.5 weeks, 2 months, 3 months, 5 months, and 12 months, respectively. Normal plasma homocysteine, normal tyrosine. Normal S-adenosylmethionine, and S-adenosylhomocysteine.

CaseGenotypingMethod: WES

Variant: NM_000429.2:c.776C>T (p.Ala259Val) (heterozygous)

ClinVar: 279845

gnomAD: The highest population minor allele frequency in gnomAD is 0.00006437 (African)

VariantEvidence: In the dimerization domain, like p.R264H. 80% reduction of the MAT activity

CaseAddInfo: The variant is maternally inherited. The mother had a mild elevation of methionine of 50 μmol/L (normal range 10–42) at 27 years of age; this was normal on repeat at 28 years old (33 umol/L) Transaminases were normal on both occasions, but she had a history of elevated liver enzymes as a child including a hepatitis-like illness, which lasted months.

CasePMIDs:

Points: 0.5 This patient and her mother are heterozygous for a missense variant in MAT1A. The highest population minor allele frequency in gnomAD is 0.00006437 (African). The Ala259 residue is located in the dimerization interface of the protein and is predicted to act in a dominant negative fashion by interfering with the dimerization (MAT III) or tetramerization (MAT I) of the enzyme.