Table 15. [Isolated Methylmalonic Acidemia: Notable Pathogenic Variants by Gene]. - GeneReviews®

Gene ¹	Reference Sequences	DNA Nucleotide Change	Predicted Protein Change	Comment
MCEE	NM_032601.4 NP_115990.3	c.139C>T	p.Arg47Ter	Common pathogenic variant, observed in homozygous state in >50% of reported persons [Heuberger et al 2019]
NM_032601.4	c.379-644A>G	--	Deep intronic variant that creates new splice site [Waters et al 2016]
NM_032601.4 NP_115990.3	c.419del	p.Lys140ArgfsTer6	Reported in an adult w/↑ serum MMA, neurodegeneration initially attributed to Parkinson disease, dementia, & stroke [Andréasson et al 2019]
MMAA	NM_172250.3 NP_758454.1	c.433C>T	p.Arg145Ter	Common pathogenic variant, accounting for 43% of mutated alleles [Lerner-Ellis et al 2004]
c.503del	p.(Thr168MetfsTer10)	This variant resides on a common haplotype & has also been seen in Spanish persons [Martínez et al 2005]
MMAB	NM_052845.4 NP_443077.1	c.556C>T	p.Arg186Trp	Most common pathogenic variant, accounts for 33% of all alleles; seen exclusively in persons of European descent; assoc w/early onset of symptoms (age <1 yr) whether in heterozygous or homozygous state [Lerner-Ellis et al 2006]
c.700C>T	p.Gln234Ter	Cobalamin-responsive variant assoc w/late-onset disease & an attenuated phenotype [Forny et al 2021]
c.656_659del	p.Tyr219SerfsTer4	In vivo response to vitamin B₁₂ reported in heterozygotes [Hörster et al 2007, Hörster et al 2021, Forny et al 2022]
MMUT ²	NM_000255.4 NP_000246.2	c.322C>T	p.Arg108Cys	Observed in persons of Hispanic descent [Worgan et al 2006]
c.2150G>T	p.Gly717Val	More common in persons of African descent [Worgan et al 2006]
c.655A>T	p.Asn219Tyr	Observed more frequently in persons of European descent [Forny et al 2016]
c.1106G>A	p.Arg369His

Gene ¹

Reference Sequences

DNA Nucleotide Change

Predicted Protein Change

Comment

MCEE

NM_032601.4
NP_115990.3

c.139C>T

p.Arg47Ter

Common pathogenic variant, observed in homozygous state in >50% of reported persons [Heuberger et al 2019]

NM_032601.4

c.379-644A>G

Deep intronic variant that creates new splice site [Waters et al 2016]

NM_032601.4
NP_115990.3

c.419del

p.Lys140ArgfsTer6

Reported in an adult w/↑ serum MMA, neurodegeneration initially attributed to Parkinson disease, dementia, & stroke [Andréasson et al 2019]

MMAA

NM_172250.3
NP_758454.1

c.433C>T

p.Arg145Ter

Common pathogenic variant, accounting for 43% of mutated alleles [Lerner-Ellis et al 2004]

c.503del

p.(Thr168MetfsTer10)

This variant resides on a common haplotype & has also been seen in Spanish persons [Martínez et al 2005]

MMAB

NM_052845.4
NP_443077.1

c.556C>T

p.Arg186Trp

Most common pathogenic variant, accounts for 33% of all alleles; seen exclusively in persons of European descent; assoc w/early onset of symptoms (age <1 yr) whether in heterozygous or homozygous state [Lerner-Ellis et al 2006]

c.700C>T

p.Gln234Ter

Cobalamin-responsive variant assoc w/late-onset disease & an attenuated phenotype [Forny et al 2021]

c.656_659del

p.Tyr219SerfsTer4

In vivo response to vitamin B₁₂ reported in heterozygotes [Hörster et al 2007, Hörster et al 2021, Forny et al 2022]

MMUT ²

NM_000255.4
NP_000246.2

c.322C>T

p.Arg108Cys

Observed in persons of Hispanic descent [Worgan et al 2006]

c.2150G>T

p.Gly717Val

More common in persons of African descent [Worgan et al 2006]

c.655A>T

p.Asn219Tyr

Observed more frequently in persons of European descent [Forny et al 2016]

c.1106G>A

p.Arg369His

From: Isolated Methylmalonic Acidemia

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Adam MP, Feldman J, Mirzaa GM, et al., editors.

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