rs193302880

chr11-119026053-G-A

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.898C>T(p.Arg300Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000621 in 1,449,120 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. R300H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SLC37A4 ENST00000330775.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 9.37

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]

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 chr11-119026052-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862
• PP5: Variant 11-119026053-G-A is Pathogenic according to our data. 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. Variant chr11-119026053-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC37A4	NM_001164277.2	c.898C>T	p.Arg300Cys	missense_variant	9/11	ENST00000642844.3
SLC37A4	NM_001164279.2	c.679C>T	p.Arg227Cys	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC37A4	ENST00000330775.9	c.898C>T	p.Arg300Cys	missense_variant	8/10	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000132 AC: 3 AN: 226760 Hom.: 0 AF XY: 0.00000817 AC XY: 1 AN XY: 122382

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: 0.0000358

Gnomad FIN exome AF: 0.0000496

Gnomad NFE exome AF: 0.00000992

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000621 AC: 9 AN: 1449120 Hom.: 0 Cov.: 31 AF XY: 0.00000417 AC XY: 3 AN XY: 719612

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: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000724

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 15, 2021	NM_001164277.1(SLC37A4):c.898C>T(R300C) is a missense variant classified as likely pathogenic in the context of glycogen storage disease type Ib. R300C has been observed in cases with relevant disease (PMID: 27848944, 10482962, Chan_2021_(no PMID; article), Bindi_2021_(no PMID; article)). Functional assessments of this variant are available in the literature (PMID: 18835800, 12444104). R300C has been observed in population frequency databases (gnomAD: FIN 0.005%). In summary, NM_001164277.1(SLC37A4):c.898C>T(R300C) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 23, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Human Genetics	Jun 23, 2020	disease causing -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 04, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 300 of the SLC37A4 protein (p.Arg300Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive glycogen storage disease (PMID: 10482962, 27848944, 35834487; Invitae). ClinVar contains an entry for this variant (Variation ID: 68293). 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, 18835800). This variant disrupts the p.Arg300 amino acid residue in SLC37A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9781688, 10940311, 12444104, 15906092). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Pathogenic	33
Dann	Benign	0.94
DEOGEN2	Uncertain	0.57	D;D;D;D
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.86	D;D;D;D
PrimateAI	Uncertain	0.67	T
Sift4G	Pathogenic	0.0	D;D;D;D
Vest4		0.91
MVP		0.49
MPC		0.24
GERP RS		5.4
gMVP		0.90

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: rs193302880; hg19: chr11-118896763;