VCV000016093.13 - ClinVar

NM_000340.2(SLC2A2):c.901C>T (p.Arg301Ter)

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.

(6)

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_000340.2(SLC2A2):c.901C>T (p.Arg301Ter)

Variation ID: 16093 Accession: VCV000016093.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3q26.2 3: 171005347 (GRCh38) [ NCBI UCSC ] 3: 170723136 (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	Aug 16, 2018	Feb 14, 2024	Apr 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000340.2:c.901C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000331.1:p.Arg301Ter	nonsense
NM_001278658.2:c.544C>T	NP_001265587.1:p.Arg182Ter	nonsense
NM_001278659.2:c.382C>T	NP_001265588.1:p.Arg128Ter	nonsense
NC_000003.12:g.171005347G>A
NC_000003.11:g.170723136G>A
NG_008108.1:g.26633C>T

... more HGVS ... less HGVS

Protein change

R301*, R182*, R128*

Other names

Canonical SPDI

NC_000003.12:171005346:G:A

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00004

Links

ClinGen: CA020034 OMIM: 138160.0004 dbSNP: rs121909743 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.
SLC2A2		-	-	GRCh38 GRCh37	302	324

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.
Fanconi-Bickel syndrome	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Apr 13, 2023	RCV000017473.43
Fanconi-Bickel syndrome Type 2 diabetes mellitus	Pathogenic (1)	criteria provided, single submitter	Dec 23, 2021	RCV002496390.3

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 (Sep 19, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Fanconi-Bickel syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000915036.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (4) PubMed: 24718840‚ 27487919‚ 22145468‚ 11810292 Comment: The SLC2A2 c.901C>T (p.Arg301Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg301Ter variant has … (more) The SLC2A2 c.901C>T (p.Arg301Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg301Ter variant has been reported in at least four studies in which it is found in a total of 17 individuals with Fanconi-Bickel syndrome, including in 16 in a homozygous state and in one in a compound heterozygous state with a nonsense variant (Santer et al. 2002; Su et al. 2011; Fridman et al. 2014; Dweikat et al. 2016). The variant was also found in a heterozygous state in two unaffected individuals (Su et al. 2011). Control data are unavailable for this variant, which is reported at a frequency of 0.000102 in the Ashkenazi Jewish population of the Genome Aggregation Database but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of stop-gained variants and the evidence from the literature, the p.Arg301Ter variant is classified as pathogenic for Fanconi-Bickel syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (May 12, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi-Bickel syndrome Affected status: yes Allele origin: germline	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001428626.1 First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020	Number of individuals with the variant: 1
Pathogenic (Dec 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Type 2 diabetes mellitus Fanconi-Bickel syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002816839.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Apr 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi-Bickel syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002020702.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Apr 09, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Fanconi-Bickel syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003525377.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 11810292‚ 9354798‚ 24718840‚ 27487919 Comment: This sequence change creates a premature translational stop signal (p.Arg301) in the SLC2A2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg301) in the SLC2A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC2A2 are known to be pathogenic (PMID: 11810292). This variant is present in population databases (rs121909743, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Fanconi-Bickel syndrome (PMID: 9354798, 24718840, 27487919). ClinVar contains an entry for this variant (Variation ID: 16093). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 01, 2002)	no assertion criteria provided Method: literature only	FANCONI-BICKEL SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000037745.3 First in ClinVar: Apr 04, 2013 Last updated: Aug 16, 2018	Publications: PubMed (4) PubMed: 15397919‚ 13480676‚ 9354798‚ 11810292 Steinmann, B., Zeller, L. Personal (more...) Steinmann, B., Zeller, L. Personal Communication. 1997. Zurich and Santa Maria Calanca, Switzerland Comment on evidence: In a patient with Fanconi-Bickel syndrome (FBS; 227810) originally reported by Fanconi and Bickel (1949) and later by Gitzelmann (1957), Santer et al. (1997) described … (more) In a patient with Fanconi-Bickel syndrome (FBS; 227810) originally reported by Fanconi and Bickel (1949) and later by Gitzelmann (1957), Santer et al. (1997) described a homozygous C-to-T transition (CGA to TGA) at nucleotide 1213 in exon 6, causing a nonsense arg301-to-ter (R301X) mutation. (In an erratum to Santer et al. (1997), the authors pointed out that the transition as noted in the paper at nucleotide 1251 was incorrect, but that the amino acid mutation was correctly reported as R301X.) This change predicted a truncated GLUT2 protein with only 6 of the 12 membrane-spanning segments. At age 52 years, the patient was 140 cm tall and still lived in a remote valley of the southern Swiss Alps. He showed persistent clinical and chemical features of FBS. His consanguineous parents had died at ages 75 and 73 years; there was no evidence of diabetes mellitus (Steinmann and Zeller, 1997). Santer et al. (2002) stated that they had found this mutation, which involves a CpG dinucleotide, in 4 unrelated families. (less)

Comment:

The SLC2A2 c.901C>T (p.Arg301Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg301Ter variant has been reported in at least four studies in which it is found in a total of 17 individuals with Fanconi-Bickel syndrome, including in 16 in a homozygous state and in one in a compound heterozygous state with a nonsense variant (Santer et al. 2002; Su et al. 2011; Fridman et al. 2014; Dweikat et al. 2016). The variant was also found in a heterozygous state in two unaffected individuals (Su et al. 2011). Control data are unavailable for this variant, which is reported at a frequency of 0.000102 in the Ashkenazi Jewish population of the Genome Aggregation Database but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of stop-gained variants and the evidence from the literature, the p.Arg301Ter variant is classified as pathogenic for Fanconi-Bickel syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

This sequence change creates a premature translational stop signal (p.Arg301*) in the SLC2A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC2A2 are known to be pathogenic (PMID: 11810292). This variant is present in population databases (rs121909743, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Fanconi-Bickel syndrome (PMID: 9354798, 24718840, 27487919). ClinVar contains an entry for this variant (Variation ID: 16093). For these reasons, this variant has been 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
Fanconi-Bickel syndrome in two Palestinian children: marked phenotypic variability with identical mutation.	Dweikat IM	BMC research notes	2016	PMID: 27487919
Phenotypic variability in patients with fanconi-bickel syndrome with identical mutations.	Fridman E	JIMD reports	2015	PMID: 24718840
Two cases of Fanconi-Bickel syndrome: first report from China with novel mutations of SLC2A2 gene.	Su Z	Journal of pediatric endocrinology & metabolism : JPEM	2011	PMID: 22145468
The mutation spectrum of the facilitative glucose transporter gene SLC2A2 (GLUT2) in patients with Fanconi-Bickel syndrome.	Santer R	Human genetics	2002	PMID: 11810292
Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome.	Santer R	Nature genetics	1997	PMID: 9354798
[The glucagon problem in glycogenosis].	GITZELMANN R	Helvetica paediatrica acta	1957	PMID: 13480676
[Chronic aminoaciduria (amino acid diabetes or nephrotic-glucosuric dwarfism) in glycogen storage and cystine disease].	FANCONI G	Helvetica paediatrica acta	1949	PMID: 15397919
Steinmann, B., Zeller, L. Personal Communication. 1997. Zurich and Santa Maria Calanca, Switzerland	-	-	-	-

Text-mined citations for rs121909743 ...

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_000340.2(SLC2A2):c.901C>T (p.Arg301Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121909743 ...