SLC25A19

protein-coding

solute carrier family 25 member 19, the group of Solute carrier family 25

Gene summary

This gene encodes a mitochondrial protein that is a member of the solute carrier family. Although this protein was initially thought to be the mitochondrial deoxynucleotide carrier involved in the uptake of deoxynucleotides into the matrix of the mitochondria, further studies have demonstrated that this protein instead functions as the mitochondrial thiamine pyrophosphate carrier, which transports thiamine pyrophosphates into mitochondria. Mutations in this gene cause microcephaly, Amish type, a metabolic disease that results in severe congenital microcephaly, severe 2-ketoglutaric aciduria, and death within the first year. Multiple alternatively spliced variants, encoding the same protein, have been identified for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

MCPHA

MANE transcript

NM_001126121.2

Inheritance

ClinVar variants

P:14U:77B:46

Top phenotype

Thiamine metabolism dysfunction syndrome 4; Microcephaly, Amish type

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr17:75,272,981-75,289,510

External References & Databases

Ensembl (ENSG00000125454)

Transcript & Mutation Effects

hg38 • Region Span ~16.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

progressive demyelinating neuropathy with bilateral striatal necrosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013382

Submitter: Labcorp Genetics (formerly Invitae)

Amish lethal microcephalySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011790

Submitter: Labcorp Genetics (formerly Invitae)

Leigh syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between SLC25A19 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of June 8, 2020. The SLC25A19 gene encodes a mitochondrial thiamine pyrophosphate carrier, and mediates uptake of thiamine pyrophosphate (TPP) into mitochondria. Pathogenic variants in SLC25A19 have been associated mainly with two phenotypes – Amish microcephaly and Leigh syndrome spectrum. The SLC25A19 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2009 (PMID: 19798730). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five variants identified in five cases in four publications (PMIDs: 19798730, 31506564, 31295743, 28856750). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function and a model system (PMIDs: 18280798, 17035501). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel June 8, 2020 (SOP Version 7).

Amish lethal microcephalySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011790

Submitter: G2P

Amish lethal microcephalySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011790

Submitter: PanelApp Australia

Amish lethal microcephalySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011790

Submitter: Orphanet

progressive demyelinating neuropathy with bilateral striatal necrosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013382

Submitter: Orphanet

progressive demyelinating neuropathy with bilateral striatal necrosisLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013382

Submitter: PanelApp Australia

progressive demyelinating neuropathy with bilateral striatal necrosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013382

Submitter: Genomics England PanelApp

Amish lethal microcephalySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011790

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Thiamine metabolism dysfunction syndrome 4; Microcephaly, Amish typeAR

Manifestation: Biochemical; Neurologic

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

Comments: High fat diet has been reported as being beneficial

Refs: 12185364; 19798730; 20583149

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC25A19 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 119

Inborn genetic diseasesTotal: 43

not specifiedTotal: 22

Amish lethal microcephalyTotal: 20

Progressive demyelinating neuropathy with bilateral striatal necrosisTotal: 17

SLC25A19-related disorderTotal: 12

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001126121.2. 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				37 clinvar		37
missense	9 clinvar	4 clinvar	73 clinvar	9 clinvar		95
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)	1 clinvar		3 clinvar			4
Total	10	4	77	46	0	137

Highest pathogenic variant AF is 0.000025403671

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 97 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001126121.2	RefSeq	NP_001119593.1	6	MANE Select
ENST00000416858.7	Ensembl	ENSP00000397818.2	6	MANE Select
NM_001126122.2	RefSeq	NP_001119594.1	6	Standard
NM_021734.5	RefSeq	NP_068380.3	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vitamin B1 (thiamin) metabolism
Purine metabolism
Metabolism
Metabolism of water-soluble vitamins and cofactors
Pyrimidine metabolism

Biological Process

deoxynucleotide transport
thiamine pyrophosphate transmembrane transport
thiamine-containing compound metabolic process
thiamine transmembrane transport

Molecular Function

thiamine transmembrane transporter activity
deoxynucleotide transmembrane transporter activity
thiamine pyrophosphate transmembrane transporter activity

Cellular Component

nucleus
mitochondrial inner membrane
integral component of mitochondrial inner membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000402418
Coding exons: 6
Length: 16519
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 125748
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.587	171	194	0.881	0.0000121	2082
Missense (PolyPhen)		31	54.564	0.56814		564
Synonymous	0.539	74	80.1	0.923	0.00000547	654
Loss of Function	2.68	2	12.0	0.166	5.19e-7	157

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000079	0.000079	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mitochondrial transporter mediating uptake of thiamine pyrophosphate (ThPP) into mitochondria. {ECO:0000269|PubMed:18280798}.;
Disease: DISEASE: Thiamine metabolism dysfunction syndrome 4, bilateral striatal degeneration and progressive polyneuropathy type (THMD4) [MIM:613710]: A disease characterized by recurrent episodes of flaccid paralysis and encephalopathy associated with bilateral striatal necrosis and chronic progressive polyneuropathy. {ECO:0000269|PubMed:19798730}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.178

Intolerance Scores

LoFtool: 0.128
RVIS EVS: -0.43
RVIS percentile EVS: 25.37

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.460

Gene Damage Prediction

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