NM_001164277.2(SLC37A4):c.1243C>T (p.Arg415Ter) AND Glucose-6-phosphate transport defect

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Feb 25, 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:: RCV000007346.12

Allele description

NM_001164277.2(SLC37A4):c.1243C>T (p.Arg415Ter)

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.1243C>T (p.Arg415Ter)

HGVS:

NC_000011.10:g.119024957G>A
NG_013331.1:g.10949C>T
NM_001164277.2:c.1243C>TMANE SELECT
NM_001164278.2:c.1309C>T
NM_001164279.2:c.1024C>T
NM_001164280.2:c.1243C>T
NM_001467.6:c.1243C>T
NP_001157749.1:p.Arg415Ter
NP_001157749.1:p.Arg415Ter
NP_001157750.1:p.Arg437Ter
NP_001157751.1:p.Arg342Ter
NP_001157752.1:p.Arg415Ter
NP_001458.1:p.Arg415Ter
LRG_187t1:c.1243C>T
LRG_187:g.10949C>T
LRG_187p1:p.Arg415Ter
NC_000011.9:g.118895667G>A
NM_001164277.1:c.1243C>T
NM_001164278.1:c.1309C>T

Protein change:

R342*; ARG415TER

Links:

OMIM: 602671.0014; dbSNP: rs121908979

NCBI 1000 Genomes Browser:

rs121908979

Molecular consequence:

NM_001164277.2:c.1243C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001164278.2:c.1309C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001164279.2:c.1024C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001164280.2:c.1243C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001467.6:c.1243C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000027544	OMIM	no assertion criteria provided	Pathogenic (Sep 1, 1999)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001406760	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10482962, 10931421, 15059622, 21575371, 24385852, 28492532
SCV001737804	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 19, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15059622, 10482962 Citation Link,
SCV004202440	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 25, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

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

Citations

PubMed

Glycogen storage disease type Ib without neutropenia.

Kure S, Hou DC, Suzuki Y, Yamagishi A, Hiratsuka M, Fukuda T, Sugie H, Kondo N, Matsubara Y, Narisawa K.

J Pediatr. 2000 Aug;137(2):253-6.

PubMed [citation]

PMID:: 10931421

[Mutation in the SLC37A4 gene of glycogen storage disease type Ib in 15 families of the mainland of China].

Qiu ZQ, Lu CX, Wang W, Qiu JJ, Wei M.

Zhonghua Er Ke Za Zhi. 2011 Mar;49(3):203-8. Chinese.

PubMed [citation]

PMID:: 21575371

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000027544.3

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

Description

In patients with classic GSD type Ib (GSD1B; 232220), Veiga-da-Cunha et al. (1999) reported a T-to-C transition at nucleotide 415 in exon 8 of the G6PT1 gene, resulting in an arg415-to-ter (R415X) substitution.

#	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 Invitae, SCV001406760.5

#	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.Arg415*) in the SLC37A4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 15 amino acid(s) of the SLC37A4 protein. This variant is present in population databases (rs121908979, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease 1b (PMID: 10482962, 10931421, 15059622, 21575371). This variant is also known as 1412C>T. ClinVar contains an entry for this variant (Variation ID: 6934). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the C-terminus of the SLC37A4 protein. Other variant(s) that disrupt this region (p.Lys426Glnfs*4) have been observed in individuals with SLC37A4-related conditions (PMID: 24385852). This suggests that this may be a clinically significant region of the protein. 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, SCV001737804.1

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

Description

Variant summary: SLC37A4 c.1243C>T (p.Arg415X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.4e-05 in 249028 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC37A4 causing Glycogen Storage Disease Type Ib (4.4e-05 vs 0.0012), allowing no conclusion about variant significance. c.1243C>T has been reported in the literature in individuals affected with Glycogen Storage Disease Type Ib (e.g. Veiga-da-Cunha_1999, Kojima_2004). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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 Baylor Genetics, SCV004202440.2

#	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: Aug 4, 2024

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