NM_014252.4(SLC25A15):c.535C>T (p.Arg179Ter) AND Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Mar 27, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000006360.15

Allele description [Variation Report for NM_014252.4(SLC25A15):c.535C>T (p.Arg179Ter)]

NM_014252.4(SLC25A15):c.535C>T (p.Arg179Ter)

Gene:

SLC25A15:solute carrier family 25 member 15 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q14.11

Genomic location:

Preferred name:

NM_014252.4(SLC25A15):c.535C>T (p.Arg179Ter)

HGVS:

NC_000013.11:g.40807376C>T
NG_012248.1:g.22966C>T
NM_014252.4:c.535C>TMANE SELECT
NP_055067.1:p.Arg179Ter
NC_000013.10:g.41381512C>T
NM_014252.3:c.535C>T

Protein change:

R179*; ARG179TER

Links:

OMIM: 603861.0003; dbSNP: rs104894429

NCBI 1000 Genomes Browser:

rs104894429

Molecular consequence:

NM_014252.4:c.535C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHHS)
Synonyms:: Ornithine translocase deficiency syndrome; HHH syndrome; Ornithine translocase deficiency
Identifiers:: MONDO: MONDO:0009393; MedGen: C0268540; Orphanet: 415; OMIM: 238970

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000026542	OMIM	no assertion criteria provided	Pathogenic (May 1, 2009)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 11355015, 3407856, 19242930
SCV000054625	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 12807890, 25874378, 22649802
SCV000964944	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 26, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11552031, 10805333, 11355015, 12807890, 19242930, 24473688, 28492532
SCV001453570	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001527692	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 27, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only

Citations

PubMed

Clinical, biochemical and ultrastructural study on the pathogenesis of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.

Nakajima M, Ishii S, Mito T, Takeshita K, Takashima S, Takakura H, Inoue I, Saheki T, Akiyoshi H, Ichihara K.

Brain Dev. 1988;10(3):181-5.

PubMed [citation]

PMID:: 3407856

The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome.

Martinelli D, Diodato D, Ponzi E, Monné M, Boenzi S, Bertini E, Fiermonte G, Dionisi-Vici C.

Orphanet J Rare Dis. 2015 Mar 11;10:29. doi: 10.1186/s13023-015-0242-9. Review.

PubMed [citation]

PMID:: 25874378
PMCID:: PMC4358699

See all PubMed Citations (11)

Details of each submission

From OMIM, SCV000026542.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

In 2 unrelated Japanese patients with HHH syndrome (238970), Miyamoto et al. (2001) identified a homozygous mutation in the SLC25A15 gene, resulting in an arg179-to-ter (R179X) substitution. One of the patients had been reported by Nakajima et al. (1988).

Tessa et al. (2009) identified homozygosity for the R179X mutation in affected members of 2 unrelated families with HHH syndrome from Senegal and Morocco, respectively. Both children from Senegal had neonatal onset of lethargy and coma. One had pyramidal signs and mild mental retardation, whereas the other had a more severe phenotype with seizures, pyramidal signs, mental retardation, and coagulopathy. In the Moroccan family, 1 child had onset in infancy of lethargy and coma, and later had liver involvement and coagulopathy, but the other child, who was homozygous for the R179X mutation, had no symptoms by age 4 years.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000054625.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000964944.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change creates a premature translational stop signal (p.Arg179*) in the SLC25A15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC25A15 are known to be pathogenic (PMID: 11552031, 19242930). This variant is present in population databases (rs104894429, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (PMID: 10805333, 11355015, 12807890, 19242930, 24473688). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5994). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001453570.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001527692.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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