NM_001164277.2(SLC37A4):c.1015G>T (p.Gly339Cys) AND Glucose-6-phosphate transport defect

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Mar 28, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000007330.28

Allele description [Variation Report for NM_001164277.2(SLC37A4):c.1015G>T (p.Gly339Cys)]

NM_001164277.2(SLC37A4):c.1015G>T (p.Gly339Cys)

Gene:

SLC37A4:solute carrier family 37 member 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q23.3

Genomic location:

Preferred name:

NM_001164277.2(SLC37A4):c.1015G>T (p.Gly339Cys)

Other names:

1184G>T

HGVS:

NC_000011.10:g.119025299C>A
NG_013331.1:g.10607G>T
NM_001164277.2:c.1015G>TMANE SELECT
NM_001164278.2:c.1081G>T
NM_001164279.2:c.796G>T
NM_001164280.2:c.1015G>T
NM_001467.6:c.1015G>T
NP_001157749.1:p.Gly339Cys
NP_001157749.1:p.Gly339Cys
NP_001157750.1:p.Gly361Cys
NP_001157751.1:p.Gly266Cys
NP_001157752.1:p.Gly339Cys
NP_001458.1:p.Gly339Cys
LRG_187t1:c.1015G>T
LRG_187:g.10607G>T
LRG_187p1:p.Gly339Cys
NC_000011.9:g.118896009C>A
NM_001164277.1:c.1015G>T
NM_001467.4:c.1015G>T
p.G339C

Protein change:

G266C; GLY339CYS

Links:

UniProtKB/Swiss-Prot: VAR_003185; OMIM: 602671.0001; dbSNP: rs80356490

NCBI 1000 Genomes Browser:

rs80356490

Molecular consequence:

NM_001164277.2:c.1015G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001164278.2:c.1081G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001164279.2:c.796G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001164280.2:c.1015G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001467.6:c.1015G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Glucose-6-phosphate transport defect (GSD1B)
Synonyms:: Glycogen storage disease type 1B; GSD Ib
Identifiers:: MONDO: MONDO:0009288; MedGen: C0268146; Orphanet: 364; Orphanet: 79259; OMIM: 232220

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000027528	OMIM	no assertion criteria provided	Pathogenic (Dec 15, 1997)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000040884	GeneReviews	no classification provided	not provided	germline	literature only
SCV000817446	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 19, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9428641, 9758626, 10482962, 10923042, 12444104, 28492532
SCV000920218	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 9, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9758626, 12444104, 18835800 Citation Link,
SCV001193861	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 9, 2019)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9758626, 10923042, 10940311, 12444104 Citation Link,
SCV001457662	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV004202431	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 28, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sequence of a putative glucose 6-phosphate translocase, mutated in glycogen storage disease type Ib.

Gerin I, Veiga-da-Cunha M, Achouri Y, Collet JF, Van Schaftingen E.

FEBS Lett. 1997 Dec 15;419(2-3):235-8.

PubMed [citation]

PMID:: 9428641

The putative glucose 6-phosphate translocase gene is mutated in essentially all cases of glycogen storage disease type I non-a.

Veiga-da-Cunha M, Gerin I, Chen YT, Lee PJ, Leonard JV, Maire I, Wendel U, Vikkula M, Van Schaftingen E.

Eur J Hum Genet. 1999 Sep;7(6):717-23.

PubMed [citation]

PMID:: 10482962

See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000027528.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 22-year-old female patient with type Ib glycogen storage disease (GSD1B; 232220), Gerin et al. (1997) demonstrated homozygosity for a gly339-to-cys (G339C) substitution in the glucose 6-phosphate transporter.

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

From GeneReviews, SCV000040884.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

#	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 Invitae, SCV000817446.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 339 of the SLC37A4 protein (p.Gly339Cys). This variant is present in population databases (rs80356490, gnomAD 0.01%). This missense change has been observed in individual(s) with glycogen storage disease (PMID: 9428641, 9758626, 10482962, 10923042). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of European ancestry (PMID: 9428641, 9758626, 10482962, 10923042). This variant is also known as c.1184G>T. ClinVar contains an entry for this variant (Variation ID: 6921). 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) performed at Invitae indicates that this missense variant is expected to disrupt SLC37A4 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC37A4 function (PMID: 12444104). For these reasons, this variant has been classified as Pathogenic.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000920218.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: The SLC37A4 c.1015G>T (p.Gly339Cys) variant causes a missense change located in the Major facilitator superfamily domain (IPR020846) (InterPro) involving the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant. Functional studies showed that this variant is associated with 4.9% of the microsomal G6P wildtype uptake activity and 5.1% of the WT Pi uptake activity in proteoliposomes (Chen_2002, Chen_2008). This variant was found in 20/272082 control chromosomes in gnomAD at a frequency of 0.0000735, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC37A4 variant (0.0012247). This variant was reported in multiple patients with GSD types Ib and Ic in compound heterozygotes and homozygotes (Veiga-da-Cunha_1998). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

#	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

From Myriad Genetics, Inc., SCV001193861.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

NM_001164277.1(SLC37A4):c.1015G>T(G339C) is classified as pathogenic in the context of glycogen storage disease type Ib. Sources cited for classification include the following: PMID 9758626, 10923042, 10940311 and 12444104. Classification of NM_001164277.1(SLC37A4):c.1015G>T(G339C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

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

From Natera, Inc., SCV001457662.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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

From Baylor Genetics, SCV004202431.2

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

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

Last Updated: Sep 16, 2024

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