VCV000006000.7 - ClinVar

NM_014252.4(SLC25A15):c.95C>G (p.Thr32Arg)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_014252.4(SLC25A15):c.95C>G (p.Thr32Arg)

Variation ID: 6000 Accession: VCV000006000.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q14.11 13: 40799096 (GRCh38) [ NCBI UCSC ] 13: 41373232 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Feb 14, 2024	May 30, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_014252.4:c.95C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055067.1:p.Thr32Arg	missense
NR_038258.1:n.2251G>C		non-coding transcript variant
NR_038259.1:n.2080G>C		non-coding transcript variant
NC_000013.11:g.40799096C>G
NC_000013.10:g.41373232C>G
NG_012248.1:g.14686C>G

... more HGVS ... less HGVS

Protein change

T32R

Other names

Canonical SPDI

NC_000013.11:40799095:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA340495 OMIM: 603861.0009 dbSNP: rs121908536 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SLC25A15		-	-	GRCh38 GRCh37	444	504

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	May 30, 2022	RCV000006366.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 30, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003442208.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 16940241 Comment: Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these … (more) Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC25A15 function (PMID: 16940241). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 6000). This missense change has been observed in individual(s) with HHH syndrome (PMID: 16940241). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 32 of the SLC25A15 protein (p.Thr32Arg). (less)
Pathogenic (Dec 11, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	HYPERORNITHINEMIA-HYPERAMMONEMIA-HOMOCITRULLINURIA SYNDROME Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV001443691.1 First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020	Comment: This variant has been previously reported as a homozygous change in patients with Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome (PMID: 16940241). In vitro overexpression studies of this variant showed … (more) This variant has been previously reported as a homozygous change in patients with Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome (PMID: 16940241). In vitro overexpression studies of this variant showed that it diminished but does not completely abolish SLC25A15 protein function (PMID: 16940241). Additional studies using fibroblasts from patients carrying this variant in the homozygous state also showed a reduction in protein function (PMID: 16940241). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.95C>G (p.Thr32Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.95C>G (p.Thr32Arg) variant is classified as Pathogenic. (less)
Pathogenic (Oct 01, 2006)	no assertion criteria provided Method: literature only	HHH SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026548.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 16940241 Comment on evidence: In 5 affected members of 2 related families of Mexican descent with HHH syndrome (238970), Camacho et al. (2006) identified a homozygous C-to-G transversion in … (more) In 5 affected members of 2 related families of Mexican descent with HHH syndrome (238970), Camacho et al. (2006) identified a homozygous C-to-G transversion in exon 3 of the SLC25A15 gene, resulting in a thr32-to-arg (T32R) substitution in a conserved residue in the first hydrophilic loop facing the mitochondrial matrix. The mutation was not found in 116 control individuals. Overexpression studies showed that the mutant protein targeted normally to the mitochondrial and retained some residual activity. However, basal ornithine transport of primary untransfected patient fibroblasts showed loss of function; the observations were important, since they showed a discordance between the clinical and cellular phenotype in patients with HHH syndrome. The patients showed phenotypic variability, with 1 patient in particular having neurologic involvement, including poor school performance, low IQ (55), dysarthria, hyperreflexia, and cortical atrophy on MRI. This patient died from complications of hyperammonemic encephalopathy. The other patients had mild learning disabilities but no neurologic deficits. Two patients with the mildest defects were found to be carriers for a gain of function val181-to-gly (V181G) polymorphism in the ORNT2 gene (SLC25A2; 608157), whereas the members of the family who had the patient with the more severe phenotype had the wildtype val181 ORNT2 variant. The mitochondrial haplotypes of the 2 families also differed. Camacho et al. (2006) suggested that the genotype of HHH patients cannot predict the clinical course of the disease, and that other modifying factors, such as gene redundancy or mitochondrial background may further influence the phenotype. (less)
not provided (-)	no classification provided Method: literature only	Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000054637.4 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 22649802‚ 10369256 BookShelf: NBK97260 BookShelf: NBK97260

Comment:

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC25A15 function (PMID: 16940241). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 6000). This missense change has been observed in individual(s) with HHH syndrome (PMID: 16940241). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 32 of the SLC25A15 protein (p.Thr32Arg).

Comment:

This variant has been previously reported as a homozygous change in patients with Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome (PMID: 16940241). In vitro overexpression studies of this variant showed that it diminished but does not completely abolish SLC25A15 protein function (PMID: 16940241). Additional studies using fibroblasts from patients carrying this variant in the homozygous state also showed a reduction in protein function (PMID: 16940241). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.95C>G (p.Thr32Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.95C>G (p.Thr32Arg) variant is classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome.	Adam MP	-	2020	PMID: 22649802
Clinical and functional characterization of a human ORNT1 mutation (T32R) in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome.	Camacho JA	Pediatric research	2006	PMID: 16940241
Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter.	Camacho JA	Nature genetics	1999	PMID: 10369256

Text-mined citations for rs121908536 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_014252.4(SLC25A15):c.95C>G (p.Thr32Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908536 ...