rs80356491

Positions:

• chr11-119025270-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The ENST00000330775.9(SLC37A4):​c.1042_1043del​(p.Leu348ValfsTer53) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,612,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L348L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SLC37A4 ENST00000330775.9 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 8.71

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-119025270-CAG-C is Pathogenic according to our data. Variant chr11-119025270-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 6926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119025270-CAG-C is described in Lovd as [Pathogenic]. Variant chr11-119025270-CAG-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC37A4	NM_001164277.2	c.1042_1043del	p.Leu348ValfsTer53	frameshift_variant	10/11	ENST00000642844.3	NP_001157749.1
SLC37A4	NM_001164279.2	c.823_824del	p.Leu275ValfsTer53	frameshift_variant	10/11		NP_001157751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC37A4	ENST00000330775.9	c.1042_1043del	p.Leu348ValfsTer53	frameshift_variant	9/10	5		ENSP00000476242	P1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000167 AC: 41 AN: 246170 Hom.: 0 AF XY: 0.000172 AC XY: 23 AN XY: 133586

Gnomad AFR exome AF: 0.0000657

Gnomad AMR exome AF: 0.000322

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.000169

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000189

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.000175 AC: 256 AN: 1460488 Hom.: 0 AF XY: 0.000182 AC XY: 132 AN XY: 726420

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000315

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000193

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74486

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000400 Hom.: 0

Bravo AF: 0.000159

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glucose-6-phosphate transport defect Pathogenic:10 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jul 03, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 19, 2019	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 14, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Oct 26, 2021	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate, PM3 very strong, PP1 supporting, PP4 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Nov 08, 2022	PVS1, PS4, PM2, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 24, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 20, 2017	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2024	Frameshift variant predicted to result in abnormal protein length as the last 82 amino acids are replaced with 52 different amino acids, and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 18437526, 30609409, 31508908, 37147621, 34946936, 34775139, 25971127, 15953877, 9758626, 9781688, 32005221, 31536830, 34426522, 34093448, 31589614, 33977030, 35433171, 35822097, 38087503, 37275680, 38531056, 35620924, 38605407, 36964972, 36039216, 37779861, 10323254, 22899091, 38259611, 10923042, 26913919, 10026167, 38818036, 28224773) -

Phosphate transport defect Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.020%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000006926 / PMID: 9781688). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Congenital disorder of glycosylation, type IIw Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Aug 10, 2022

The c.1042_1043del;p.(Leu348Valfs*53) is a null frameshift variant (NMD) in the SLC37A4 gene without sufficient information about prediction of nonsense mediated mRNA decay (NMD); it is present in a relevant exon to the transcript, and disrupts >10% of the protein product – PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(Clinvar ID: 6926; PMID: 20301489; 28224773; 26913919; 22899091; 15953877) - PS4. The variant is present at low allele frequencies population databases (rs80356491 – gnomAD 0.002562%; ABraOM 0.002562 frequency - https://abraom.ib.usp.br/) -PM2_supporting.The p.(Leu348Valfs*53) was detected in trans with a pathogenic variant (PMID: 22899091; 26913919; 28224773) - PM3_strong. In summary, the currently available evidence indicates that the variant is pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2015

- -

Glycogen storage disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 24, 2017

The p.Leu348ValfsX53 (NM_001164277.1 c.1042_1043delCT) variant in SLC37A4 (also referred to as c.1211delCT in the literature) has been reported in at least 3 ho mozygous and 10 compound heterozygous individuals with clinical features of Glyc ogen storage disease type I (GSDI) (Veiga da Cunha 1998, Janecke 1999, and Sante r 2000). This variant is reported as Pathogenic by three sources in ClinVar (Var iation ID#6926). This variant has also been identified in 13/57880 of European c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs80356491). Although this variant has been seen in the general popu lation, its frequency is low enough to be consistent with a recessive carrier fr equency. This variant is predicted to cause a frameshift, which alters the prote in?s amino acid sequence beginning at position 348 and leads to a premature term ination codon 53 amino acids downstream. This alteration is then predicted to le ad to a truncated or absent protein. Biallelic loss of function of the SLC37A4 gene has been associated with Glycogen storage disease type I (GSDI). In summary , the p.Leu348ValfsX53 variant in SLC37A4 meets criteria for pathogenic for GSDI in an autosomal recessive manner based upon its biallelic occurrence in patient s with this disease and predicted functional impact. -

Glycogen storage disease, type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Breakthrough Genomics, Breakthrough Genomics

Jul 23, 2020

The SLC37A4 c.1042_1043delCT variant (also referred to as c.1211delCT in the literature) was previously reported in homozygous or compound heterozygous state in various ethnic individuals affected with glycogen storage disease and was classified as pathogenic variant [PMID: 9758626, 10026167, 10923042, 10323254, 15953877, 22899091, 26913919, 28224773]. Additionally, this variant was found to be segregated with GSDI disease phenotype in multiple family studies [PMID: 9758626, 10026167]. -

Glucose-6-phosphate transport defect;C0342749:Phosphate transport defect;C5561986:Congenital disorder of glycosylation, type IIw Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

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: rs80356491; hg19: chr11-118895980;