NM_000340.2:c.1094G>A

SLC2A2 · NP_000331.1:p.(Arg365Gln) · NM_000340.2

GRCh37: chr3:170716930 C>T · GRCh38: chr3:170999141 C>T

Gene: SLC2A2 Transcript: NM_000340.2

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

SLC2A2

Transcript

NM_000340.2

Protein

NP_000331.1:p.(Arg365Gln)

gnomAD AF

1.9852742284107633e-05 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

PVS1 is not applicable. NM_000340.2:c.1094G>A is a missense variant (p.Arg365Gln), not a null variant meeting ClinGen SVI PVS1 criteria.

PM2 (Supporting) is met. The variant is present in gnomAD at extremely low frequency — v2.1 AF 2.13e-05 (6/282,168 alleles), v4.1 AF 1.99e-05 (32/1,611,868 alleles), grpmax FAF 1.13e-05 to 8.17e-05 — well below the 0.1% threshold. Absent from gnomAD-Canada. Zero homozygotes observed.

PP3 (Supporting) is met. Multiple computational predictors support a deleterious effect: REVEL score 0.84 (strongly pathogenic range, >0.5), BayesDel no-AF score 0.352 (above deleterious threshold >0.27). SpliceAI predicts no splicing impact (delta 0.0), consistent with a coding missense variant.

No pathogenic criteria beyond PM2 and PP3 (both supporting) are met. No benign criteria are met. All moderate, strong, and very strong criteria are either not applicable, not assessed, or not met.

Per ACMG/AMP 2015 combination rules (PMID:25741868), two supporting pathogenic criteria (PM2_Supporting + PP3_Supporting) are insufficient to reach Likely Pathogenic. The variant is classified as a Variant of Uncertain Significance (VUS).

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	PVS1 is not applicable: NM_000340.2:c.1094G>A is a missense variant (p.Arg365Gln) and does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants.	pvs1_generic_framework
PS1	Not assessed	No evidence of a different nucleotide change at codon 365 producing the same amino acid substitution (p.Arg365Gln) classified as pathogenic was identified. No ClinVar records exist for this variant or same-residue comparators.
PS2	Not assessed	No de novo data are available for this variant. No publications or database records report a de novo occurrence of NM_000340.2:c.1094G>A.
PS3	Not assessed	No variant-specific functional studies were identified for NM_000340.2:c.1094G>A (p.Arg365Gln). REVEL and BayesDel are in silico predictors, not well-established functional assays. COSMIC reports one somatic occurrence (COSV100049434) which does not constitute germline functional evidence.
PS4	Not assessed	No case-control or statistical enrichment data are available. The variant is absent from ClinVar and no published case series specifically reporting this variant were identified.
PS5	N/A	PS5 is not a criterion in the ACMG/AMP 2015 framework; it was removed from the classification rubric.
PM1	Not met	Residue Arg365 does not lie in a statistically significant mutational hotspot per CancerHotspots.org. No functional domain annotation from OncoKB is available to support localization to a critical domain.	oncokb
PM2	Met	NM_000340.2:c.1094G>A is present in gnomAD at extremely low allele frequency: v2.1 AF 2.13e-05 (6/282,168 alleles, grpmax FAF 1.13e-05) and v4.1 AF 1.99e-05 (32/1,611,868 alleles, grpmax FAF 8.17e-05), well below the 0.1% PM2 threshold. No homozygotes observed. This is an autosomal recessive disorder (Fanconi-Bickel syndrome), and very low population frequency is consistent with pathogenicity.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 requires a different pathogenic missense change at the same residue. No same-residue comparator variants (at Arg365) classified as pathogenic were identified in ClinVar. PM5 candidate harvesting was unable to confirm classic same-residue semantics.	pm5_candidates
PM6	Not assessed	No de novo data are available. PM6 requires a confirmed de novo occurrence with confirmed maternity and paternity. No such reports were identified for NM_000340.2:c.1094G>A.
PP1	Not assessed	No cosegregation data are available. No family studies reporting segregation of NM_000340.2:c.1094G>A with Fanconi-Bickel syndrome or other SLC2A2-related phenotypes were identified.
PP2	Not assessed	No gene-level constraint metrics (e.g., missense Z-score, gnomAD o/e) are available for SLC2A2 to determine whether the gene has a low rate of benign missense variation. PP2 cannot be applied without these data.
PP3	Met	Multiple lines of computational evidence support a deleterious effect. REVEL score of 0.84 is strongly predictive of pathogenicity (threshold >0.5). BayesDel no-AF score of 0.352 is above the deleterious threshold of 0.27. SpliceAI predicts no splicing impact (max delta = 0.0), which is expected for a coding missense variant and does not negate the REVEL and BayesDel predictions.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or clinical data are available for the individual(s) carrying this variant. PP4 requires that the patient's phenotype or family history is highly specific for the disease associated with the gene.
PP5	Not met	PP5 requires a reputable source to have reported the variant as pathogenic with evidence unavailable for independent evaluation. NM_000340.2:c.1094G>A is absent from ClinVar; no reputable source has classified this variant.	clinvar
BA1	Not met	BA1 requires allele frequency >1% in population databases. The highest observed population frequency is 0.015% (gnomAD v4.1 African/African American), far below the 1% threshold.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires allele frequency >0.3% in population databases. The variant frequency (~0.002%) is far below this threshold.	gnomad_v2 gnomad_v4
BS2	Not met	For recessive disorders, BS2 requires observation of the variant in homozygous state in healthy adults. No homozygotes are observed in gnomAD (0 homozygotes across v2.1 and v4.1 combined). BS2 is not met.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional studies demonstrating no deleterious effect of p.Arg365Gln on GLUT2 protein function were identified.
BS4	Not assessed	No segregation data are available to assess lack of segregation with disease.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. SLC2A2 is associated with Fanconi-Bickel syndrome and neonatal diabetes, with both missense and truncating variants reported as disease-causing. Published SLC2A2 disease cohorts include missense variants as pathogenic.
BP2	Not assessed	No data available on observation in trans with a pathogenic variant (for dominant disorders) or in cis with a pathogenic variant.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact. REVEL score of 0.84 strongly supports a deleterious effect, directly conflicting with BP4. While SpliceAI shows no splice impact (delta = 0.0) and BayesDel is intermediate (0.352), the strong REVEL prediction precludes BP4 application.	revel bayesdel spliceai
BP5	Not assessed	No data available on the variant being found in a case with an alternative molecular basis for disease.
BP6	Not met	BP6 requires a reputable source to report the variant as benign. The variant is absent from ClinVar and no reputable source has classified it as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_000340.2:c.1094G>A is a missense variant (p.Arg365Gln), not synonymous.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.