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NM_014252.4(SLC25A15):c.337G>A (p.Gly113Ser) AND Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

Germline classification:
Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:
Feb 8, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV001113456.12

Allele description [Variation Report for NM_014252.4(SLC25A15):c.337G>A (p.Gly113Ser)]

NM_014252.4(SLC25A15):c.337G>A (p.Gly113Ser)

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.337G>A (p.Gly113Ser)
HGVS:
  • NC_000013.11:g.40805140G>A
  • NG_012248.1:g.20730G>A
  • NM_014252.4:c.337G>AMANE SELECT
  • NP_055067.1:p.Gly113Ser
  • NC_000013.10:g.41379276G>A
  • NM_014252.3:c.337G>A
Protein change:
G113S
Links:
dbSNP: rs199894905
NCBI 1000 Genomes Browser:
rs199894905
Molecular consequence:
  • NM_014252.4:c.337G>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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001271229Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)
Uncertain significance
(Jan 13, 2018)
germlineclinical testing

Citation Link,

SCV001577929Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 19, 2024)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV004201672Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 8, 2024)
unknownclinical testing

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

Summary from all submissions

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

Citations

PubMed

Hyperornithinemia, Hyperammonemia, and Homocitrullinuria Syndrome Causing Severe Neonatal Hyperammonemia.

Wild KT, Ganetzky RD, Yudkoff M, Ierardi-Curto L.

JIMD Rep. 2019;44:103-107. doi: 10.1007/8904_2018_132. Epub 2018 Sep 6.

PubMed [citation]
PMID:
30187369
PMCID:
PMC6323011

HHH syndrome (hyperornithinaemia, hyperammonaemia, homocitrullinuria), with fulminant hepatitis-like presentation.

Fecarotta S, Parenti G, Vajro P, Zuppaldi A, Della Casa R, Carbone MT, Correra A, Torre G, Riva S, Dionisi-Vici C, Santorelli FM, Andria G.

J Inherit Metab Dis. 2006 Feb;29(1):186-9.

PubMed [citation]
PMID:
16601889
See all PubMed Citations (7)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001271229.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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

From Invitae, SCV001577929.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 113 of the SLC25A15 protein (p.Gly113Ser). This variant is present in population databases (rs199894905, gnomAD 0.01%). This missense change has been observed in individual(s) with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (PMID: 30187369, 30243302). 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: 883225). 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. This variant disrupts the p.Gly113 amino acid residue in SLC25A15. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16601889, 19242930, 26589310, 30243302). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

From Baylor Genetics, SCV004201672.2

#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