rs193302903

chr11-119026052-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The ENST00000330775.9(SLC37A4):c.899G>A(p.Arg300His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,560 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R300C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC37A4 ENST00000330775.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.39

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 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in ENST00000330775.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-119026053-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846
• PP5: Variant 11-119026052-C-T is Pathogenic according to our data. Variant chr11-119026052-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119026052-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC37A4	NM_001164277.2	c.899G>A	p.Arg300His	missense_variant	9/11	ENST00000642844.3
SLC37A4	NM_001164279.2	c.680G>A	p.Arg227His	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC37A4	ENST00000330775.9	c.899G>A	p.Arg300His	missense_variant	8/10	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448560 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719296

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: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glucose-6-phosphate transport defect Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 02, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 300 of the SLC37A4 protein (p.Arg300His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive SLC37A4-related conditions (PMID: 9781688, 15906092). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 68294). 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: 10940311, 12444104). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 03, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jul 05, 2023	PS3, PM2, PM3, PM5 -

not provided Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

Glycogen storage disease type 1 due to SLC37A4 mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Jan 05, 2022

The c.899G>A;p.(Arg300His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID:68294; PMID: 15906092; 9781688) - PS4_moderateWell-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 12444104; 10940311) - PS3_supporting. This variant is not present in population databases (rs193302903, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Arg300His) was detected in trans with a pathogenic variant (PMID: 15906092; 9781688) - PM3_strong. Pathogenic missense variant in this residue have been reported (ClinVar ID: 68293) - PM5. In summary, the currently available evidence indicates that the variant is pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 02, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
Cadd	Pathogenic	30
Dann	Benign	0.94
DEOGEN2	Uncertain	0.51	D;D;D;D
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.85	D;D;D;D
PrimateAI	Uncertain	0.62	T
Sift4G	Pathogenic	0.0	D;D;D;D
Vest4		0.90
MVP		0.39
MPC		0.23
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.87

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: rs193302903; hg19: chr11-118896762; COSMIC: COSV100421525; COSMIC: COSV100421525;