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NM_014252.4(SLC25A15):c.564C>G (p.Phe188Leu) AND Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

Germline classification:
Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:
Mar 8, 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:
RCV000031951.12

Allele description [Variation Report for NM_014252.4(SLC25A15):c.564C>G (p.Phe188Leu)]

NM_014252.4(SLC25A15):c.564C>G (p.Phe188Leu)

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.564C>G (p.Phe188Leu)
HGVS:
  • NC_000013.11:g.40807405C>G
  • NG_012248.1:g.22995C>G
  • NM_014252.4:c.564C>GMANE SELECT
  • NP_055067.1:p.Phe188Leu
  • NC_000013.10:g.41381541C>G
  • NM_014252.3:c.564C>G
  • Q9Y619:p.Phe188Leu
Protein change:
F188L
Links:
UniProtKB: Q9Y619#VAR_058952; dbSNP: rs141028076
NCBI 1000 Genomes Browser:
rs141028076
Molecular consequence:
  • NM_014252.4:c.564C>G - 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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001215767Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Feb 16, 2023)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV001424487Centogene AG - the Rare Disease Company
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenicgermlineclinical testing

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

SCV002086772Natera, Inc.
no assertion criteria provided
Likely pathogenic
(Nov 3, 2020)
germlineclinical testing

SCV004201692Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Mar 8, 2024)
unknownclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study.

Tessa A, Fiermonte G, Dionisi-Vici C, Paradies E, Baumgartner MR, Chien YH, Loguercio C, de Baulny HO, Nassogne MC, Schiff M, Deodato F, Parenti G, Rutledge SL, Vilaseca MA, Melone MA, Scarano G, Aldamiz-Echevarría L, Besley G, Walter J, Martinez-Hernandez E, Hernandez JM, Pierri CL, et al.

Hum Mutat. 2009 May;30(5):741-8. doi: 10.1002/humu.20930.

PubMed [citation]
PMID:
19242930

Clinical utility of exome sequencing in individuals with large homozygous regions detected by chromosomal microarray analysis.

Prasad A, Sdano MA, Vanzo RJ, Mowery-Rushton PA, Serrano MA, Hensel CH, Wassman ER.

BMC Med Genet. 2018 Mar 20;19(1):46. doi: 10.1186/s12881-018-0555-3.

PubMed [citation]
PMID:
29554876
PMCID:
PMC5859484
See all PubMed Citations (9)

Details of each submission

From Invitae, SCV001215767.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 188 of the SLC25A15 protein (p.Phe188Leu). This variant is present in population databases (rs141028076, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of SLC25A15-related conditions (PMID: 19242930, 29554876). ClinVar contains an entry for this variant (Variation ID: 38399). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC25A15 protein function. Experimental studies have shown that this missense change affects SLC25A15 function (PMID: 25818551, 26589310). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Phe188 amino acid residue in SLC25A15. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10369256, 12807890, 23430880). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

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

From Centogene AG - the Rare Disease Company, SCV001424487.1

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

From Natera, Inc., SCV002086772.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV004201692.2

#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