rs80356490

Variant names:

• chr11-119025299-C-A
• rs80356490
• ENST00000330775.9:c.1015G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM5 PP3_Moderate PP5_Very_Strong

The ENST00000330775.9(SLC37A4):​c.1015G>T​(p.Gly339Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,611,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G339D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: SLC37A4 ENST00000330775.9 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:2
• Conservation: PhyloP100: 7.37
• Publications: 22 publications found

Genes affected

SLC37A4 (HGNC:4061): (solute carrier family 37 member 4) This gene regulates glucose-6-phosphate transport from the cytoplasm to the lumen of the endoplasmic reticulum, in order to maintain glucose homeostasis. It also plays a role in ATP-mediated calcium sequestration in the lumen of the endoplasmic reticulum. Mutations in this gene have been associated with various forms of glycogen storage disease. Alternative splicing in this gene results in multiple transcript variants.[provided by RefSeq, Aug 2009]

TRAPPC4 (HGNC:19943): (trafficking protein particle complex subunit 4) Involved in autophagy and endoplasmic reticulum to Golgi vesicle-mediated transport. Part of TRAPP complex. [provided by Alliance of Genome Resources, Apr 2022]

TRAPPC4 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-119025298-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant 11-119025299-C-A is Pathogenic according to our data. Variant chr11-119025299-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC37A4	NM_001164278.2	c.1081G>T	p.Gly361Cys	missense_variant	Exon 11 of 12		NP_001157750.1
SLC37A4	NM_001164277.2	c.1015G>T	p.Gly339Cys	missense_variant	Exon 10 of 11		NP_001157749.1
SLC37A4	NM_001164280.2	c.1015G>T	p.Gly339Cys	missense_variant	Exon 8 of 9		NP_001157752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC37A4	ENST00000330775.9	c.1015G>T	p.Gly339Cys	missense_variant	Exon 9 of 10	5		ENSP00000476242.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000779 AC: 19 AN: 243898 AF XY: 0.0000680

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000942

Gnomad NFE exome AF: 0.000136

Gnomad OTH exome AF: 0.000338

GnomAD4 exome AF: 0.000105 AC: 153 AN: 1459216 Hom.: 0 Cov.: 34 AF XY: 0.0000978 AC XY: 71 AN XY: 725700

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00 AC: 0 AN: 85818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000134 AC: 149 AN: 1110758

Other (OTH) AF: 0.0000664 AC: 4 AN: 60280

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.0000910 AC: 11

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glucose-6-phosphate transport defect Pathogenic:6 Other:1

Nov 09, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 15, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:4 Other:1

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 22, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9428641, 10940311, 18835800, 19008136, 20578944, 12811562, 10482962, 21599942, 31980526, 31589614, 33977030, 12444104, 9758626, 12373566) -

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	31
DANN	Benign	0.94
DEOGEN2	Uncertain	0.61	D;D;D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.92	D;D;D;D
PhyloP100		7.4
PrimateAI	Pathogenic	0.81	D
Sift4G	Pathogenic	0.0	D;D;D;D
Vest4		0.98
MVP		0.74
MPC		0.22
GERP RS		5.0
gMVP		0.95
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80356490; hg19: chr11-118896009;