rs781784543

Positions:

• chr11-119026979-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000330775.9(SLC37A4):​c.742C>T​(p.Gln248Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,472 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SLC37A4 ENST00000330775.9 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.36

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-119026979-G-A is Pathogenic according to our data. Variant chr11-119026979-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC37A4	NM_001164277.2	c.742C>T	p.Gln248Ter	stop_gained	7/11	ENST00000642844.3	NP_001157749.1
SLC37A4	NM_001164279.2	c.523C>T	p.Gln175Ter	stop_gained	7/11		NP_001157751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC37A4	ENST00000330775.9	c.742C>T	p.Gln248Ter	stop_gained	6/10	5		ENSP00000476242	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000241 AC: 6 AN: 248734 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 134970

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461472 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727002

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glucose-6-phosphate transport defect Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jul 05, 2023	PVS1, PM2, PM3 -
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	Jul 28, 2016	Variant summary: The SLC37A4 c.742C>T (p.Gln248X) 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 2/118148 control chromosomes at a frequency of 0.0000169, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC37A4 variant (0.0012247). This variant has been reported in multiple GSD type 1b patients both homozygously and heterozygously. In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic, without evidence to independently evaluate. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 28, 2023	This sequence change creates a premature translational stop signal (p.Gln248*) in the SLC37A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC37A4 are known to be pathogenic (PMID: 9758626, 10940311). This variant is present in population databases (rs781784543, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with glycogen storage disease type Ib (PMID: 9758626, 10026167, 18437526). ClinVar contains an entry for this variant (Variation ID: 188762). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Apr 21, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 28, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 09, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2018	The Q248X pathogenic variant in the SLC37A4 gene has been reported previously in association with glycogen storage disease type 1b when present in the homozygous state or when in trans with another pathogenic variant (Veiga-da-Cunha et al., 1998; Melis et al., 2005; Jun et al., 2014). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q248X variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret Q248X as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	44
DANN	Benign	0.93
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.97
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs781784543; hg19: chr11-118897689;