NM_000340.2:c.115_117del

SLC2A2 · NP_000331.1:p.(Ile39del) · NM_000340.2

GRCh37: chr3:170732511 ATAT>A · GRCh38: chr3:171014722 ATAT>A

Gene: SLC2A2 Transcript: NM_000340.2

Final call

VUS

PM2 supporting PM4 supporting PP5 supporting

Variant details

Gene

SLC2A2

Transcript

NM_000340.2

Protein

NP_000331.1:p.(Ile39del)

gnomAD AF

1.3643140105126597e-05 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000340.2:c.115_117del (p.Ile39del) is an in-frame deletion of a single amino acid in exon 3 of SLC2A2, encoding the GLUT2 glucose transporter. Loss-of-function variants in SLC2A2 cause Fanconi-Bickel syndrome (autosomal recessive) and have been implicated in neonatal diabetes.

This variant is present at extremely low frequency in population databases: gnomAD v2.1 allele frequency 0.00284% (8/282,066 alleles, 0 homozygotes) and v4.1 allele frequency 0.00136% (22/1,612,532 alleles, 0 homozygotes). It is absent from gnomAD-Canada.

The variant has been classified as Likely pathogenic in ClinVar (Variation ID: 631915) by two independent clinical testing laboratories, with Fulgent Genetics providing ACMG criteria with their submission.

As an in-frame deletion in a non-repeat region, PM4 (supporting) applies. The variant does not qualify for PVS1, as it is not a null variant (nonsense, frameshift, or canonical splice site).

No variant-specific literature was identified among the four ClinVar-linked PMIDs. PMID:25741868 (ACMG/AMP guidelines) and PMID:22962670 (hypertriglyceridemia guideline) were reviewed in full text; neither mentions NM_000340.2:c.115_117del or SLC2A2. PMID:20301750 (WFS1 Spectrum Disorder) and PMID:23492873 (EGAPP diabetes risk recommendations) are unrelated to this variant.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_000340.2:c.115_117del is an in-frame 3-bp deletion (p.Ile39del), which does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The ClinGen SVI PVS1 framework does not apply to in-frame deletions.	pvs1_generic_framework
PS1	N/A	PS1 applies to a different nucleotide change producing the same amino acid change as an established pathogenic variant. This variant is an in-frame deletion (p.Ile39del), not a missense substitution, and no established pathogenic single-nucleotide variant at the same residue was identified.
PS2	Not assessed	No de novo occurrence data were identified for this variant in ClinVar submissions or the reviewed literature.
PS3	Not assessed	One ClinVar submission (SCV004120392, PreventionGenetics) mentions functional studies suggesting impaired glucose uptake, but this submission has no assertion criteria, no validated PMIDs, and the cited study could not be verified. No variant-specific functional study was identified in the reviewed literature.
PS4	Not assessed	Insufficient case-control or prevalence data to compare affected versus general population frequencies. SLC2A2-related disease (Fanconi-Bickel syndrome) is autosomal recessive, complicating standard PS4 application.
PS5	N/A	PS5 applies when a different pathogenic variant at the same residue has been established from a reputable source. This is an in-frame deletion, not a missense change, and no known pathogenic missense at residue I39 was identified.
PM1	Not assessed	This variant does not lie in a statistically significant mutational hotspot (evidence_brief hotspots: not significant). No curated functional domain or critical-residue data were identified for SLC2A2 residue I39.
PM2	Met	NM_000340.2:c.115_117del is present at extremely low frequency in gnomAD: v2.1 allele frequency 0.00284% (8/282,066 alleles, 0 homozygotes) and v4.1 allele frequency 0.00136% (22/1,612,532 alleles, 0 homozygotes). Absent from gnomAD-Canada. The allele frequency is well below the 0.1% threshold for PM2.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	Met	NM_000340.2:c.115_117del (p.Ile39del) is an in-frame deletion of a single amino acid in exon 3 of SLC2A2, not located in a known repetitive region. In-frame deletions in non-repeat regions meet PM4 at supporting strength per ClinGen SVI guidance.	pvs1_generic_framework
PM5	N/A	PM5 applies to a novel missense change at the same amino acid residue as a known pathogenic missense variant. This is an in-frame deletion, not a missense change, and PM5 candidate harvesting found no eligible comparators.
PM6	Not assessed	No de novo occurrence data (with or without confirmed paternity) were identified for this variant.
PP1	Not assessed	No cosegregation data were identified for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This is an in-frame deletion, not a missense variant.
PP3	Not assessed	In silico prediction tools (REVEL, BayesDel) were not applicable to this non-SNV variant. SpliceAI predicts no splicing impact (max delta = 0.00). HCI prior is not available for SLC2A2. No computational evidence supports a deleterious or benign effect.	spliceai
PP4	Not assessed	No patient phenotype or clinical data were available for this variant in the reviewed evidence. SLC2A2-related Fanconi-Bickel syndrome has a specific phenotype (hepatomegaly, short stature, hypophosphatemic rickets, glucose/galactose intolerance), but no phenotype-variant correlation data were identified.
PP5	Met	Two clinical testing laboratories (PreventionGenetics and Fulgent Genetics) have classified NM_000340.2:c.115_117del as Likely pathogenic in ClinVar (Variation ID: 631915). Fulgent Genetics provided ACMG criteria with their submission (SCV005661889). While no expert panel classification exists, two independent clinical laboratories agree on a likely pathogenic classification, meeting PP5 at supporting level.	clinvar
BA1	Not met	The allele frequency in gnomAD v2.1 (0.00284%) and v4.1 (0.00136%) is far below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency in gnomAD v2.1 (0.00284%) and v4.1 (0.00136%) is far below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data on homozygous or hemizygous occurrence in healthy adults were identified. SLC2A2-related disease is autosomal recessive with childhood onset; observation in healthy adults would be informative but is not available.
BS3	Not assessed	No well-established functional studies showing no deleterious effect were identified for this variant.
BS4	Not assessed	No nonsegregation data were identified for this variant.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants cause disease. This is an in-frame deletion and SLC2A2 has both missense and loss-of-function variants associated with disease (Fanconi-Bickel syndrome, neonatal diabetes).
BP2	Not assessed	No data on observation in trans with a dominant pathogenic variant were identified.
BP3	Not met	BP3 applies to in-frame deletions in repetitive regions without known function. The c.115_117del deletion removes a single isoleucine in exon 3 and is not located in a known repetitive region.
BP4	Not assessed	SpliceAI predicts no splicing impact (max delta = 0.00), but REVEL and BayesDel are not applicable to non-SNV variants. Insufficient computational evidence is available to support a benign prediction for an in-frame deletion.	spliceai
BP5	Not assessed	No data on this variant being found in a case with an alternate molecular basis for disease were identified.
BP6	Not met	BP6 requires a reputable source to classify the variant as benign. This variant is classified as Likely pathogenic in ClinVar by two clinical laboratories; it has not been reported as benign.
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is an in-frame deletion (p.Ile39del), not a synonymous variant.
PM3	N/A	Skipped per instruction; trivially not applicable.

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