chr11-119028229-G-GCC

Variant names:

• chr11-119028229-G-GCC
• rs782604758
• ENST00000330775.9:c.344_345dupGG

Variant summary

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

The NM_001164278.2(SLC37A4):​c.344_345dupGG​(p.Leu116GlyfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,605,154 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SLC37A4 NM_001164278.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.0380

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 11-119028229-G-GCC is Pathogenic according to our data. Variant chr11-119028229-G-GCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC37A4	NM_001164278.2	c.344_345dupGG	p.Leu116GlyfsTer31	frameshift_variant	Exon 4 of 12		NP_001157750.1
SLC37A4	NM_001164277.2	c.344_345dupGG	p.Leu116GlyfsTer31	frameshift_variant	Exon 4 of 11		NP_001157749.1
SLC37A4	NM_001164280.2	c.344_345dupGG	p.Leu116GlyfsTer31	frameshift_variant	Exon 2 of 9		NP_001157752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC37A4	ENST00000330775.9	c.344_345dupGG	p.Leu116GlyfsTer31	frameshift_variant	Exon 3 of 10	5		ENSP00000476242.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000428 AC: 1 AN: 233828 Hom.: 0 AF XY: 0.00000789 AC XY: 1 AN XY: 126700

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000948

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1452950 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 721768

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: 0.00000451

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glucose-6-phosphate transport defect Pathogenic:5

Mar 03, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 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.344_345dupGG (p.Leu116GlyfsX31) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.3e-06 in 233828 control chromosomes. c.344_345dupGG has been reported in the literature in multiple individuals affected with Glycogen Storage Disease Type Ib (examples- Galli_1999, Sperb-Ludwig_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 10, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 19, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu116Glyfs*31) 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 (rs782604758, gnomAD 0.001%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease (PMID: 10518030). ClinVar contains an entry for this variant (Variation ID: 550962). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

See cases Pathogenic:1

Apr 14, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1, PS4, PM2, PM3 -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs782604758; hg19: chr11-118898939;