ENST00000330775.9:c.547T>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The ENST00000330775.9(SLC37A4):c.547T>C(p.Cys183Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,554 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: 34)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SLC37A4
ENST00000330775.9 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 8.73

Publications

6 publications found

Variant links:

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]

SLC37A4 Gene-Disease associations (from GenCC):

congenital disorder of glycosylation, type IIw
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
glycogen storage disease Ib
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
glycogen storage disease type 1 due to SLC37A4 mutation
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health

SLC37A4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.869

PP5

Variant 11-119027706-A-G is Pathogenic according to our data. Variant chr11-119027706-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 68284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
SLC37A4	NM_001164278.2 link	c.547T>C	p.Cys183Arg	missense_variant	Exon 6 of 12	NP_001157750.1	O43826-2A0A024R3L1
SLC37A4	NM_001164277.2 link	c.547T>C	p.Cys183Arg	missense_variant	Exon 6 of 11	NP_001157749.1	O43826-1A0A024R3H9A8K0S7
SLC37A4	NM_001164280.2 link	c.547T>C	p.Cys183Arg	missense_variant	Exon 4 of 9	NP_001157752.1	O43826-1A0A024R3H9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC37A4	ENST00000330775.9 link	c.547T>C	p.Cys183Arg	missense_variant	Exon 5 of 10	5		ENSP00000476242.2		U3KPU7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000415

AC:

AN:

240882

AF XY:

0.00

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000919

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727042

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111810

Other (OTH)

AF:

0.00

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glucose-6-phosphate transport defect

Pathogenic:2

Jan 22, 2022

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.547T>C, legacy nucleotide naming as T716C in exon 3 (p.Cys183Arg) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Two of two in-silico tools predict a damaging effect of the variant on protein function while three in-silico tools did not provide a prediction. The variant allele was found at a frequency of 4.2e-06 in 240882 control chromosomes. c.547T>C has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Glycogen Storage Disease Type Ib (example, Veiga-da-Cunha_1999, Galli_1999, Hiraiwa_1999, Janecke_2000, Sperb-Ludwig_2019). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function (example, Hiraiwa_1999, Chen_2002). The most pronounced variant effect results in a complete disruption of microsomal glucose-6-phosphate (G6P) uptake resulting from defective transport. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 183 of the SLC37A4 protein (p.Cys183Arg). This variant is present in population databases (rs193302893, gnomAD 0.0009%). This missense change has been observed in individual(s) with glycogen storage disease (PMID: 10482962, 10518030, 15906092, 16435186). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as T716C, c.716T>C. ClinVar contains an entry for this variant (Variation ID: 68284). 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 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). For these reasons, this variant has been classified as Pathogenic. -

Congenital disorder of glycosylation, type IIw

Pathogenic:1

Nov 21, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

0.99

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.62

CADD

Uncertain

(source)

DANN

Benign

0.87

DEOGEN2

Uncertain

0.43

T;T;T;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

.;D;D;D

M_CAP

Benign

0.048

MetaRNN

Pathogenic

0.87

D;D;D;D

PhyloP100

8.7

PrimateAI

Pathogenic

0.81

Sift4G

Uncertain

0.0040

D;D;D;D

Vest4

0.99

MVP

0.59

MPC

0.25

GERP RS

5.2

gMVP

0.96

Mutation Taster

=0/100

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over