NM_001164277.2(SLC37A4):c.1042_1043del (p.Leu348fs) AND Glucose-6-phosphate transport defect

Germline classification:: Pathogenic (11 submissions)
Last evaluated:: Mar 24, 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:: RCV000007336.40

Allele description [Variation Report for NM_001164277.2(SLC37A4):c.1042_1043del (p.Leu348fs)]

NM_001164277.2(SLC37A4):c.1042_1043del (p.Leu348fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

11q23.3

Genomic location:

Preferred name:

NM_001164277.2(SLC37A4):c.1042_1043del (p.Leu348fs)

Other names:

1211delCT; p.Leu370ValfsTer53

HGVS:

NC_000011.10:g.119025271_119025272del
NG_013331.1:g.10634_10635del
NM_001164277.2:c.1042_1043delMANE SELECT
NM_001164278.2:c.1108_1109del
NM_001164279.2:c.823_824del
NM_001164280.2:c.1042_1043del
NM_001467.6:c.1042_1043del
NP_001157749.1:p.Leu348fs
NP_001157749.1:p.Leu348fs
NP_001157750.1:p.Leu370fs
NP_001157751.1:p.Leu275fs
NP_001157752.1:p.Leu348fs
NP_001458.1:p.Leu348fs
LRG_187t1:c.1042_1043del
LRG_187:g.10634_10635del
LRG_187p1:p.Leu348fs
NC_000011.9:g.118895981_118895982del
NC_000011.9:g.118895981_118895982delAG
NM_001164277.1:c.1042_1043del
NM_001164277.1:c.1042_1043delCT
NM_001164278.1:c.1108_1109delCT
NM_001164278.2:c.1108_1109del
NM_001164280.1:c.1042_1043delCT
NM_001467.4:c.1042_1043delCT
NM_001467.5:c.1042_1043delCT
NM_001467.6:c.1042_1043del
NP_001458.1:p.Leu348ValfsTer53
p.Leu370ValfsX53

Protein change:

L275fs

Links:

OMIM: 602671.0006; dbSNP: rs80356491

NCBI 1000 Genomes Browser:

rs80356491

Molecular consequence:

NM_001164277.2:c.1042_1043del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001164278.2:c.1108_1109del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001164279.2:c.823_824del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001164280.2:c.1042_1043del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001467.6:c.1042_1043del - frameshift variant - [Sequence Ontology: SO:0001589]

Functional consequence:

protein truncation [Variation Ontology: 0015]

Observations:

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
SCV000027534	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 1999)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 9758626, 10323254
SCV000040885	GeneReviews	no classification provided	not provided	germline	literature only
SCV000680381	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Nov 20, 2017)	germline	clinical testing	Citation Link,
SCV000697753	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 14, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9758626, 24646511, 10026167, 10323254 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000755870	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10923042, 15953877, 22899091, 26913919, 28224773, 28492532
SCV001193826	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 19, 2019)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9758626, 10923042, 10940311 Citation Link,
SCV002078640	Natera, Inc.	no assertion criteria provided	Pathogenic (Feb 3, 2020)	germline	clinical testing
SCV002098318	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 3, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002512368	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 26, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004013976	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 8, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004202432	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 24, 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	unknown	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	germline	yes	1	not provided	not provided	1	not provided	clinical testing, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Hindu	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Involvement of endocrine system in a patient affected by glycogen storage disease 1b: speculation on the role of autoimmunity.

Melis D, Della Casa R, Balivo F, Minopoli G, Rossi A, Salerno M, Andria G, Parenti G.

Ital J Pediatr. 2014 Mar 19;40(1):30. doi: 10.1186/1824-7288-40-30.

PubMed [citation]

PMID:: 24646511
PMCID:: PMC3974180

Inactivation of the glucose 6-phosphate transporter causes glycogen storage disease type 1b.

Hiraiwa H, Pan CJ, Lin B, Moses SW, Chou JY.

J Biol Chem. 1999 Feb 26;274(9):5532-6.

PubMed [citation]

PMID:: 10026167

See all PubMed Citations (12)

Details of each submission

From OMIM, SCV000027534.2

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

Description

In 2 families, Veiga-da-Cunha et al. (1998) found that patients with glycogen storage disease Ib (GSD1B; 232220) were homozygous for a 2-bp deletion (1211-1212delCT) in the G6PT1 gene, resulting in a change in reading frame after ala347.

This common frameshift mutation was reported by Veiga-da-Cunha et al. (1998) to be present in 8 GSD Ib patients. In a Turkish patient with GSD Ic (GSD1C; 232240), Janecke et al. (1999) identified the same mutation. Thus, GSD Ib and Ic result from the same mutation of the same gene.

#	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, SCV000040885.3

#	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 Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV000680381.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	yes	1	blood	not provided		1	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697753.1

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

Description

Variant summary: The SLC37A4 c.1042_1043delCT (p.Leu348Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent SLC37A4 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 24/103512 control chromosomes at a frequency of 0.0002319, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC37A4 variant (0.0012247). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic.The variant was identified in multiple affected individuals homozygously or in compound heterozygosity in patients with clinically and biochemically confirmed Glycogen Storage Disease Type 1b (GSD1b). Multiple family studies showed segregation of this variant with GSD1b (Veiga-de-Cunha_AJHG_1998; Hiraiwa_J. Biol. Chem.-1999). 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 Invitae, SCV000755870.8

#	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 creates a premature translational stop signal (p.Leu348Valfs*53) in the SLC37A4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 82 amino acid(s) of the SLC37A4 protein. This variant is present in population databases (rs80356491, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with glycogen storage disease (PMID: 10923042, 15953877, 22899091, 26913919, 28224773). ClinVar contains an entry for this variant (Variation ID: 6926). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 Myriad Genetics, Inc., SCV001193826.2

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

Description

NM_001164277.1(SLC37A4):c.1042_1043delCT(L348Vfs*53, aka 1211delCT) is classified as pathogenic in the context of glycogen storage disease type Ib. Sources cited for classification include the following: PMID 9758626, 10923042 and 10940311. Classification of NM_001164277.1(SLC37A4):c.1042_1043delCT(L348Vfs*53, aka 1211delCT) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. 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., SCV002078640.1

#	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 Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV002098318.1

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

Description

A homozygous 2 base pair deletion in exon 11 of the SLC37A4 gene that results in frameshift and premature truncation of the protein 53 amino acids downstream to codon 370. The observed variant c.1108_1109del (p.Leu370ValfsTer53) has not been reported in the 1000 genomes and has a MAF of 0.03% in the gnomAD databases. The in silico prediction of the variant are damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a pathogenic variant.

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

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV002512368.1

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

Description

ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate, PM3 very strong, PP1 supporting, PP4 supporting

#	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 Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV004013976.1

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

Description

PVS1, PS4, PM2, PP5

#	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 Baylor Genetics, SCV004202432.2

#	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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