rs193302892

Variant names:

• chr11-119027808-C-T
• rs193302892
• ENST00000330775.9:c.446G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001164278.2(SLC37A4):​c.446G>A​(p.Gly149Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 1,457,168 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SLC37A4 NM_001164278.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.38

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity G6PT1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001164278.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842
• PP5: Variant 11-119027808-C-T is Pathogenic according to our data. Variant chr11-119027808-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 68280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119027808-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC37A4	NM_001164278.2	c.446G>A	p.Gly149Glu	missense_variant	Exon 5 of 12		NP_001157750.1
SLC37A4	NM_001164277.2	c.446G>A	p.Gly149Glu	missense_variant	Exon 5 of 11		NP_001157749.1
SLC37A4	NM_001164280.2	c.446G>A	p.Gly149Glu	missense_variant	Exon 3 of 9		NP_001157752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC37A4	ENST00000330775.9	c.446G>A	p.Gly149Glu	missense_variant	Exon 4 of 10	5		ENSP00000476242.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000292 AC: 7 AN: 239678 Hom.: 0 AF XY: 0.0000154 AC XY: 2 AN XY: 130058

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000404

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000892 AC: 13 AN: 1457168 Hom.: 0 Cov.: 34 AF XY: 0.00000414 AC XY: 3 AN XY: 724498

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000278

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glucose-6-phosphate transport defect Pathogenic:5

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2024

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 glutamic acid, which is acidic and polar, at codon 149 of the SLC37A4 protein (p.Gly149Glu). This variant is present in population databases (rs193302892, gnomAD 0.04%). This missense change has been observed in individuals with autosomal recessive glycogen storage disease type Ib (PMID: 10026167, 10518030, 12444104, 29581464). ClinVar contains an entry for this variant (Variation ID: 68280). 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 not expected to disrupt SLC37A4 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SLC37A4 function (PMID: 10026167, 12444104). For these reasons, this variant has been classified as Pathogenic. -

Jul 24, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC37A4 c.446G>A (p.Gly149Glu) results in a non-conservative amino acid change located in the Glycerate/sugar phosphate transporter, conserved signature motif (IPR021159) of the encoded protein sequence. Two of two in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 239678 control chromosomes (gnomAD). The variant, c.446G>A, has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Glycogen Storage Disease Type Ib (e.g. Hiraiwa_1999, Galli_1999, Lam_2000, Sperb-Ludwig_2019). These data indicate that the variant is likely to be associated with disease. Several publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant almost completely abolishes the glucose-6-phosphate transport activity of the protein (e.g. Hiraiwa_1999, Chen_2002, Chen_2008). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 20, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 12, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	28
DANN	Benign	0.90
DEOGEN2	Uncertain	0.45	T;T;T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.84	D;D;D;D
PrimateAI	Pathogenic	0.85	D
Sift4G	Pathogenic	0.0	D;D;D;D
Vest4		0.99
MVP		0.52
MPC		0.19
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs193302892; hg19: chr11-118898518;