SHMT2

protein-coding

serine hydroxymethyltransferase 2, the group of Serine hydroxymethyltransferase family

Gene summary

This gene encodes the mitochondrial form of a pyridoxal phosphate-dependent enzyme that catalyzes the reversible reaction of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate. The encoded product is primarily responsible for glycine synthesis. The activity of the encoded protein has been suggested to be the primary source of intracellular glycine. The gene which encodes the cytosolic form of this enzyme is located on chromosome 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

Previous symbols:

SHMT

MANE transcript

NM_005412.6

Inheritance

ClinVar variants

P:4U:82B:12

Top phenotype

Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr12:57,229,573-57,234,935

External References & Databases

Ensembl (ENSG00000182199)

Transcript & Mutation Effects

hg38 • Region Span ~5.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030866

Submitter: PanelApp Australia

neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalitiesLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0030866

Submitter: ClinGen

*SHMT2* was first reported in relation to autosomal recessive neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (NEDCASB) in 2020 (García-Cazorla, et al., 2020, PMID:33015733). Patient fibroblasts with NEDCASB were found to have altered mitochondrial membrane potentials and ROS levels. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 8 variants (missense and single amino acid deletion) have been reported in 5 probands from 2 publication (PMID:33015733, PMID:35398349). Variants in this gene segregated with disease in 1 additional family member. The gene *SHMT2* encodes an enzyme that serves as the mitochondrial form of serine hydroxymethyltransferase. Specifically, the enzyme catalyzes the reversible reaction of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate within the mitochondria. This gene-disease association is further supported by its biochemical function in kinetic assays (PMID:30500180) and a knockdown drosophila model (PMID:33015733) and a knockout mouse model (PMID:29323231), which recapitulates the molecular phenotype of deficiencies in mitochondrial respiratoration but for which homozygous knock outs are embryonic lethal at day 13.5 post coitum. The gene-disease relationship is also supported by functional alteration and rescue in cell culture models (PMIDs:29452640, 29364879), which show that null SHMT2 cells show a deficiency in respiratory chain translation due to an inability to maintain formylmethionyl-tRNA pools. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the Aminoacidopathy GCEP on 11/11/2022, it was updated 07/02/2024 to reasses the NM_005412.6:c.1124-4_1125delinsA variant.

neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030866

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030866

Submitter: G2P

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalitiesAR

Manifestation: Cardiovascular; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: Among other findings, the condition can include progressive cardiomyopathy, and awareness may allow early diagnosis and management; Cardiac transplant has been described

Refs: 33015733

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SHMT2 variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 55

not providedTotal: 26

Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalitiesTotal: 17

SHMT2-related disorderTotal: 7

not specifiedTotal: 3

Neurodevelopmental disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005412.6. 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			1 clinvar	7 clinvar	1 clinvar	9
missense		4 clinvar	71 clinvar	3 clinvar	1 clinvar	79
nonsense			3 clinvar			3
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	0	4	82	10	2	98

Highest pathogenic variant AF is 0.0000034203704

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 67 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005412.6	RefSeq	NP_005403.2	12	MANE Select
ENST00000328923.8	Ensembl	ENSP00000333667.3	12	MANE Select
NM_001166356.2	RefSeq	NP_001159828.1	12	Standard
NM_001166357.1	RefSeq	NP_001159829.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

One carbon pool by folate - Homo sapiens (human)
Glycine, serine and threonine metabolism - Homo sapiens (human)
Glyoxylate and dicarboxylate metabolism - Homo sapiens (human)
3-Phosphoglycerate dehydrogenase deficiency
Non Ketotic Hyperglycinemia

Biological Process

regulation of oxidative phosphorylation
glycine metabolic process
L-serine metabolic process
L-serine biosynthetic process
L-serine catabolic process

Molecular Function

chromatin binding
glycine hydroxymethyltransferase activity
protein binding
zinc ion binding
L-allo-threonine aldolase activity

Cellular Component

nucleus
cytoplasm
mitochondrion
mitochondrial inner membrane
mitochondrial intermembrane space

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000328923
Coding exons: 12
Length: 5609
Individuals with no LoFs: 125711
Homozygous LoFs: 0
Heterozygous LoFs: 37
Defined: 125748
p: 0.000147

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.52	234	309	0.756	0.0000194	3234
Missense (PolyPhen)		88	137.89	0.63817		1442
Synonymous	-0.677	131	122	1.08	0.00000704	1063
Loss of Function	2.16	16	28.4	0.563	0.00000186	276

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00024	0.00023	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.00020	0.00020	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the cleavage of serine to glycine accompanied with the production of 5,10-methylenetetrahydrofolate, an essential intermediate for purine biosynthesis (PubMed:24075985, PubMed:29364879, PubMed:25619277). Serine provides the major source of folate one-carbon in cells by catalyzing the transfer of one carbon from serine to tetrahydrofolate (PubMed:25619277). Contributes to the de novo mitochondrial thymidylate biosynthesis pathway via its role in glycine and tetrahydrofolate metabolism: thymidylate biosynthesis is required to prevent uracil accumulation in mtDNA (PubMed:21876188). Also required for mitochondrial translation by producing 5,10- methylenetetrahydrofolate; 5,10-methylenetetrahydrofolate providing methyl donors to produce the taurinomethyluridine base at the wobble position of some mitochondrial tRNAs (PubMed:29452640, PubMed:29364879). Associates with mitochondrial DNA (PubMed:18063578). In addition to its role in mitochondria, also plays a role in the deubiquitination of target proteins as component of the BRISC complex: required for IFNAR1 deubiquitination by the BRISC complex (PubMed:24075985). {ECO:0000269|PubMed:18063578, ECO:0000269|PubMed:21876188, ECO:0000269|PubMed:24075985, ECO:0000269|PubMed:25619277, ECO:0000269|PubMed:29364879, ECO:0000269|PubMed:29452640}.;

Recessive Scores

pRec: 0.395

Intolerance Scores

LoFtool: 0.822
RVIS EVS: -0.11
RVIS percentile EVS: 45.26

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.923

Gene Damage Prediction

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