U.S. flag

An official website of the United States government

NM_014252.4(SLC25A15):c.538G>A (p.Glu180Lys) AND Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

Germline classification:
Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:
Feb 6, 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:
RCV000006359.9

Allele description [Variation Report for NM_014252.4(SLC25A15):c.538G>A (p.Glu180Lys)]

NM_014252.4(SLC25A15):c.538G>A (p.Glu180Lys)

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.538G>A (p.Glu180Lys)
HGVS:
  • NC_000013.11:g.40807379G>A
  • NG_012248.1:g.22969G>A
  • NM_014252.3:c.538G>A
  • NM_014252.4:c.538G>AMANE SELECT
  • NP_055067.1:p.Glu180Lys
  • NC_000013.10:g.41381515G>A
  • NM_014252.4:c.538G>A
  • Q9Y619:p.Glu180Lys
Protein change:
E180K; GLU180LYS
Links:
UniProtKB: Q9Y619#VAR_012760; OMIM: 603861.0002; dbSNP: rs104894424
NCBI 1000 Genomes Browser:
rs104894424
Molecular consequence:
  • NM_014252.4:c.538G>A - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000026541OMIM
no assertion criteria provided
Pathogenic
(Jun 1, 1999)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV001589952Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Nov 6, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004099567Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely pathogenic
(Sep 6, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV004201670Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Feb 6, 2024)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.

Capalbo A, Valero RA, Jimenez-Almazan J, Pardo PM, Fabiani M, Jiménez D, Simon C, Rodriguez JM.

PLoS Genet. 2019 Oct;15(10):e1008409. doi: 10.1371/journal.pgen.1008409.

PubMed [citation]
PMID:
31589614
PMCID:
PMC6797235
See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000026541.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In a non-French Canadian patient with HHH (238970), Camacho et al. (1999) identified apparent homozygosity for a 538G-A transition in the SLC25A15 gene, resulting in a glu180-to-lys (E180K) substitution in the predicted fourth transmembrane domain. The patient's Irish American father was an E180K heterozygote, but his Japanese mother was not. These observations, together with the different origins of the 2 parents, indicated that the patient represented a genetic compound for E180K and a second mutant ORNT1 allele that failed to amplify. Further studies suggested that the second allele in this patient carried a microdeletion involving ORNT1 inherited from the mother. The mutant E180K transporter targeted to the mitochondria, but was inactive, indicating that this substitution impairs activity without affecting targeting or stability.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001589952.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 180 of the SLC25A15 protein (p.Glu180Lys). This variant is present in population databases (rs104894424, gnomAD 0.007%). This missense change has been observed in individual(s) with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (PMID: 10369256; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5993). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC25A15 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC25A15 function (PMID: 10369256, 26589310). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004099567.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: SLC25A15 c.538G>A (p.Glu180Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251488 control chromosomes. c.538G>A has been reported in trans along with a full/partial SLC25A15 deletion in at-least one individual affected with Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome (example, Camacho_1999). This variant has also been reported in an individual undertaking a genetic carrier screening (Capalbo_2019). At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in abolishment of the rescuing ability of SLC25A15 in vitro and in vivo (Camacho_1999, Doimo_2015). The following publications have been ascertained in the context of this evaluation (PMID: 10369256, 31589614, 26589310). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (both pathogenic). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV004201670.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 17, 2024