rs80356490

chr11-119025299-C-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:2

Conservation

PhyloP100: 7.37

Variant links:

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]

SLC37A4 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-119025298-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id 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 id is 6921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119025299-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC37A4	NM_001164277.2 linkuse as main transcript	c.1015G>T	p.Gly339Cys	missense_variant	10/11	ENST00000642844.3
SLC37A4	NM_001164279.2 linkuse as main transcript	c.796G>T	p.Gly266Cys	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC37A4	ENST00000330775.9 linkuse as main transcript	c.1015G>T	p.Gly339Cys	missense_variant	9/10	5		P1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000779

AC:

AN:

243898

Hom.:

AF XY:

0.0000680

AC XY:

AN XY:

132368

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.0000978

AC XY:

AN XY:

725700

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000134

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000240

AC:

ExAC

AF:

0.0000910

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glucose-6-phosphate transport defect

Pathogenic:6Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 15, 1997	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 09, 2017	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. -

not provided

Pathogenic:4Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2021	Published functional studies demonstrate a damaging effect; mutant protein expressed in COS-1 cells abolished microsomal G6P uptake activity and compromises G6PT stability (Chen et al., 2002; Chen et al., 2000); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9758626, 12373566, 12444104, 27535533, 31980526, 21599942, 10482962, 12811562, 20578944, 19008136, 18835800, 10940311, 9428641) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.63

Cadd

Pathogenic

Dann

Benign

0.94

DEOGEN2

Uncertain

0.61

D;D;D;D

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.92

D;D;D;D

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.81

Sift4G

Pathogenic

0.0

D;D;D;D

Vest4

0.98

MVP

0.74

MPC

0.22

GERP RS

5.0

gMVP

0.95

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over