DMGDH

protein-coding

dimethylglycine dehydrogenase

Gene summary

This gene encodes an enzyme involved in the catabolism of choline, catalyzing the oxidative demethylation of dimethylglycine to form sarcosine. The enzyme is found as a monomer in the mitochondrial matrix, and uses flavin adenine dinucleotide and folate as cofactors. Mutation in this gene causes dimethylglycine dehydrogenase deficiency, characterized by a fishlike body odor, chronic muscle fatigue, and elevated levels of the muscle form of creatine kinase in serum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

MANE transcript

NM_013391.3

Inheritance

ClinVar variants

P:4U:111B:26

Top phenotype

Dimethylglycine dehydrogenase deficiency

gnomAD constraint

pLI —, LoF o/e 0.9

Max pathogenic AF

—

Genomic locus

chr5:78,997,564-79,236,038

External References & Databases

Ensembl (ENSG00000132837)

Transcript & Mutation Effects

hg38 • Region Span ~238.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

dimethylglycine dehydrogenase deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0011610

Submitter: ClinGen

*DMGDH* was first reported in relation to autosomal recessive dimethylglycine dehydrogenase deficiency in 1999 (Moolenaar et al., PMID:10102904) with the variant being identified in 2001 (Binzak et al; PMID: 11231903). This was a homozygous missense variant with functional evidence to support pathogenicity, with the phenotypes consisting of a distinctive fish-like odor, increased serum CK, muscle fatigue, and increased levels of N,N-dimethylglycine in urine. A second case was reported in 2017 (Wang XL, et al., PMID: 28881522) with a homozygous splice variant in a patient with elevated muscle enzymes, mainly CK. Evidence supporting this gene-disease relationship includes only these two case-level pieces of evidence and biochemical function data which implicates the *DMGDH* mutant's decrease in choline metabolism as potentially causal for these phenotypes. In summary, there is limited evidence to support this gene-disease relationship, particularly due to the lack of reported variants in humans. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.This classification was approved by the ClinGen Aminoacidopathy Working Group on 06/28/19 (SOP Version 6). It was reevaluated on 10/14/2022 with no new evidence found and again in 11/18/2025 when PMID: 28881522 was added. As a result of this reevaluation, the classification remains Limited.

dimethylglycine dehydrogenase deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0011610

Submitter: Labcorp Genetics (formerly Invitae)

dimethylglycine dehydrogenase deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0011610

Submitter: PanelApp Australia

dimethylglycine dehydrogenase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011610

Submitter: Orphanet

Clinical Genomic Database (CGD)

Dimethylglycine dehydrogenase deficiencyAR

Manifestation: Biochemical; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 10102904

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to DMGDH variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 128

not providedTotal: 28

DMGDH-related disorderTotal: 10

Dimethylglycine dehydrogenase deficiencyTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_013391.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	18 clinvar	1 clinvar	21
missense		2 clinvar	105 clinvar	5 clinvar	2 clinvar	114
nonsense		1 clinvar	2 clinvar			3
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar			2
Total	0	4	111	23	3	141

Highest pathogenic variant AF is 0.00030754655

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_013391.3	RefSeq	NP_037523.2	16	MANE Select
ENST00000255189.8	Ensembl	ENSP00000255189.3	16	MANE Select
ENST00000517853.5	Ensembl	ENSP00000428995.1	3	Standard
ENST00000518477.5	Ensembl	ENSP00000427834.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycine, serine and threonine metabolism - Homo sapiens (human)
3-Phosphoglycerate dehydrogenase deficiency
Non Ketotic Hyperglycinemia
Glycine and Serine Metabolism
sarcosine oncometabolite pathway

Biological Process

amino-acid betaine catabolic process
choline metabolic process
electron transport chain
choline catabolic process

Molecular Function

RNA binding
electron transfer activity
oxidoreductase activity
dimethylglycine dehydrogenase activity

Cellular Component

cytoplasm
mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000255189
Coding exons: 16
Length: 238424
Individuals with no LoFs: 125192
Homozygous LoFs: 3
Heterozygous LoFs: 553
Defined: 125748
p: 0.00221

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.563	409	442	0.925	0.0000232	5598
Missense (PolyPhen)		146	176.15	0.82885		2078
Synonymous	-0.838	174	160	1.08	0.00000876	1711
Loss of Function	0.622	39	43.4	0.898	0.00000242	532

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00098	0.00098	rare
Latino/Admixed American	0.0033	0.0032	notable
Ashkenazi Jewish	0.0017	0.0017	notable
East Asian	0.0021	0.0021	notable
Finnish	0.0012	0.0012	notable
European (Non-Finnish)	0.0021	0.0021	notable
South Asian	0.0030	0.0030	notable
Other	0.0036	0.0036	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the demethylation of N,N-dimethylglycine to sarcosine. Also has activity with sarcosine in vitro. {ECO:0000269|PubMed:27486859}.;
Disease: DISEASE: DMGDH deficiency (DMGDHD) [MIM:605850]: Disorder characterized by fish odor, muscle fatigue with increased serum creatine kinase. Biochemically it is characterized by an increase of N,N-dimethylglycine (DMG) in serum and urine. {ECO:0000269|PubMed:11231903, ECO:0000269|PubMed:27486859}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.346
RVIS EVS: 0.16
RVIS percentile EVS: 64.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.840

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	Medium	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High