NM_014251.3(SLC25A13):c.2T>C (p.Met1Thr) AND Neonatal intrahepatic cholestasis due to citrin deficiency

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 31, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002470789.7

Allele description [Variation Report for NM_014251.3(SLC25A13):c.2T>C (p.Met1Thr)]

NM_014251.3(SLC25A13):c.2T>C (p.Met1Thr)

Genes:

LOC129998833:ATAC-STARR-seq lymphoblastoid silent region 18384 [Gene]
SLC25A13:solute carrier family 25 member 13 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q21.3

Genomic location:

Preferred name:

NM_014251.3(SLC25A13):c.2T>C (p.Met1Thr)

Other names:

p.Met1?

HGVS:

NC_000007.14:g.96321955A>G
NG_012247.2:g.5193T>C
NM_001160210.2:c.2T>C
NM_014251.3:c.2T>CMANE SELECT
NP_001153682.1:p.Met1Thr
NP_055066.1:p.Met1Thr
NC_000007.13:g.95951267A>G
NM_014251.2:c.2T>C
NR_027662.2:n.144T>C

Protein change:

M1T

Links:

dbSNP: rs541276426

NCBI 1000 Genomes Browser:

rs541276426

Molecular consequence:

NM_001160210.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_014251.3:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001160210.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_014251.3:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_027662.2:n.144T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Neonatal intrahepatic cholestasis due to citrin deficiency
Synonyms:: Neonatal-onset citrullinemia type II; Neonatal intrahepatic cholestasis caused by citrin deficiency; Neonatal-onset citrullinemia type 2
Identifiers:: MONDO: MONDO:0011601; MedGen: C1853942; Orphanet: 247598; OMIM: 605814

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002768492	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 31, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 23022256, 23053473, 23067347, 25216257, 27405544, 30887117, 34704407, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002768492

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 31, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The mutation spectrum of SLC25A13 gene in citrin deficiency: identification of novel mutations in Vietnamese pediatric cohort with neonatal intrahepatic cholestasis.

Nguyen MT, Nguyen AP, Ngo DN, Nguyen PT, Tang HS, Giang H, Lu YT, Nguyen HN, Tran MD.

J Hum Genet. 2023 May;68(5):305-312. doi: 10.1038/s10038-022-01112-2. Epub 2023 Jan 4.

PubMed [citation]

PMID:: 36599957

Molecular analysis of SLC25A13 gene in human peripheral blood lymphocytes: Marked transcript diversity, and the feasibility of cDNA cloning as a diagnostic tool for citrin deficiency.

Zhang ZH, Lin WX, Deng M, Zhao XJ, Song YZ.

Gene. 2012 Dec 15;511(2):227-34. doi: 10.1016/j.gene.2012.09.049. Epub 2012 Sep 26.

PubMed [citation]

PMID:: 23022256

See all PubMed Citations (9)

Details of each submission

From Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam, SCV002546531.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768492.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neonatal-onset citrullinemia type II (MIM# 605814) and adult-onset citrullinemia type II (MIM#603471). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0206 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (84 heterozygotes, 3 homozygotes). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported multiple times as VUS in ClinVar. It has also been reported multiple times as homozygous or compound heterozygous in individuals with neonatal intrahepatic cholestasis caused by citrin deficiency (PMID: 23022256, 23067347, 25216257, 27405544, 30887117, 34704407). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies in yeast found this variant expresses a truncated protein which was not functional (PMID: 23053473). (SP) 0710 - Another start loss variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An alternative change c.2T>A has been reported as VUS in ClinVar. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002546531	Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam See additional submitters Hepatology Department, National Children’s Hospital	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Pathogenic (Jun 30, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 36599957, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002546531

Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam

See additional submitters

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Pathogenic
(Jun 30, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Last Updated: Jun 17, 2024

ClinVar

Relating variation to medicine