rs80356490

Positions:

• chr11-119025299-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001164278.2(SLC37A4):​c.1081G>T​(p.Gly361Cys) 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: SLC37A4 NM_001164278.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:2
• Conservation: PhyloP100: 7.37

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 (HGNC:):

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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	Protein	UniProt
SLC37A4	NM_001164278.2	c.1081G>T	p.Gly361Cys	missense_variant	11/12		NP_001157750.1
SLC37A4	NM_001164277.2	c.1015G>T	p.Gly339Cys	missense_variant	10/11		NP_001157749.1
SLC37A4	NM_001164280.2	c.1015G>T	p.Gly339Cys	missense_variant	8/9		NP_001157752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC37A4	ENST00000330775.9	c.1015G>T	p.Gly339Cys	missense_variant	9/10	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

GnomAD3 exomes AF: 0.0000779 AC: 19 AN: 243898 Hom.: 0 AF XY: 0.0000680 AC XY: 9 AN XY: 132368

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.: 0 Cov.: 34 AF XY: 0.0000978 AC XY: 71 AN XY: 725700

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

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.: 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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 15, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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, 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2024	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) -
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	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
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

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

Other links and lift over

dbSNP: rs80356490; hg19: chr11-118896009;