VCV000849656.35 - ClinVar

NM_014251.3(SLC25A13):c.135G>C (p.Leu45Phe)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_014251.3(SLC25A13):c.135G>C (p.Leu45Phe)

Variation ID: 849656 Accession: VCV000849656.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q21.3 7: 96277273 (GRCh38) [ NCBI UCSC ] 7: 95906585 (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 15, 2020	Jun 17, 2024	Dec 6, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_014251.3:c.135G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055066.1:p.Leu45Phe	missense
NM_001160210.2:c.135G>C	NP_001153682.1:p.Leu45Phe	missense
NR_027662.2:n.277G>C		non-coding transcript variant
NC_000007.14:g.96277273C>G
NC_000007.13:g.95906585C>G
NG_012247.2:g.49875G>C

... more HGVS ... less HGVS

Protein change

L45F

Other names

Canonical SPDI

NC_000007.14:96277272: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

dbSNP: rs1798490375 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.
SLC25A13		-	-	GRCh38 GRCh37	844	890

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.
Citrin deficiency	Uncertain significance (1)	criteria provided, single submitter	Dec 22, 2021	RCV001053667.6
Citrullinemia	Uncertain significance (1)	no assertion criteria provided	Dec 28, 2020	RCV001832490.1
Neonatal intrahepatic cholestasis due to citrin deficiency	Pathogenic (1)	criteria provided, single submitter	Jun 30, 2022	RCV002508285.4
Citrullinemia, type II, adult-onset	Likely pathogenic (1)	criteria provided, single submitter	Dec 6, 2023	RCV003467771.2

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.
Uncertain significance (Dec 22, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Citrin deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001217940.4 First in ClinVar: Apr 15, 2020 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 31845334 Comment: This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 45 of the SLC25A13 protein (p.Leu45Phe). … (more) This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 45 of the SLC25A13 protein (p.Leu45Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with citrin deficiency (PMID: 31845334). ClinVar contains an entry for this variant (Variation ID: 849656). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Pathogenic (Jun 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neonatal intrahepatic cholestasis due to citrin deficiency Affected status: yes Allele origin: germline	Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam Additional submitter: Hepatology Department, National Children’s Hospital Accession: SCV002546532.2 First in ClinVar: Jan 07, 2023 Last updated: Feb 25, 2023	Publications: PubMed (1) PubMed: 36599957
Likely pathogenic (Dec 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Citrullinemia, type II, adult-onset Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004209379.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Dec 28, 2020)	no assertion criteria provided Method: clinical testing	Citrullinemia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002079397.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022

Comment:

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 45 of the SLC25A13 protein (p.Leu45Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with citrin deficiency (PMID: 31845334). ClinVar contains an entry for this variant (Variation ID: 849656). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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
The mutation spectrum of SLC25A13 gene in citrin deficiency: identification of novel mutations in Vietnamese pediatric cohort with neonatal intrahepatic cholestasis.	Nguyen MT	Journal of human genetics	2023	PMID: 36599957
Combining newborn metabolic and genetic screening for neonatal intrahepatic cholestasis caused by citrin deficiency.	Lin Y	Journal of inherited metabolic disease	2020	PMID: 31845334

Text-mined citations for rs1798490375 ...

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_014251.3(SLC25A13):c.135G>C (p.Leu45Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1798490375 ...