Variant classification summary

NM_001360016.2:c.202G>A

G6PD · NP_001346945.1:p.(Val68Met) · NM_001360016.2

GRCh37: chrX:153764217 C>T · GRCh38: chrX:154536002 C>T

Gene: G6PD Transcript: NM_001360016.2

Final call

VUS

PS3 supporting BP2 supporting

Variant details

Gene

G6PD

Transcript

NM_001360016.2

Protein

NP_001346945.1:p.(Val68Met)

gnomAD AF

0.006443034878493799 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PS3 supporting documents reduced erythrocyte G6PD activity associated with the 202A allele.

2

VUS: BP2 supporting documents cis occurrence with p.Asn126Asp in a pathogenic haplotype.

3

VUS: the two supporting criteria satisfy neither a pathogenic nor a benign generic ACMG/AMP combination rule.

Final determination: Under the generic ACMG/AMP 2015 fallback, PS3 supporting plus BP2 supporting meets neither a pathogenic nor a benign combination threshold, resulting in VUS.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: p.Val68Met appears in a pathogenic haplotype, but no independently established pathogenic same-amino-acid variant is documented.	PMID:23006493
PS2	Not assessed	Not assessed: no documented patient phenotype, confirmed maternity and paternity, or absent family history establishes a fully confirmed de novo occurrence.
PS3	Met	Met at supporting: the 202A allele reduced erythrocyte G6PD activity by approximately 40% in heterozygotes and 80% in hemizygotes or homozygotes.	PMID:25201310 PMID:23006493
PS4	Not met	Not met: no exact-variant case-control counts support OR/RR >5.0 with a 95% confidence interval excluding 1.0.	PMID:7577654 PMID:23006493
PM1	Not assessed	Not assessed: residue 68 has no qualifying hotspot, while an authoritative G6PD critical-domain list is unavailable.	cspec hotspots cosmic
PM2	Not met	Not met: gnomAD v4.1 total AF is 0.6443% (7,797/1,210,144), far above the PM2 threshold of 0.01%.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no affected-proband or parent/offspring evidence establishes c.202G>A in trans with a pathogenic variant.	PMID:23006493
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no pathogenic alternate missense change at Val68 is documented for comparison with p.Val68Met.	pm5_candidates
PM6	Not assessed	Not assessed: no patient-level assumed de novo occurrence is documented, with neither the proband context nor incomplete parental confirmation available.
PP1	Not assessed	Not assessed: no affected family members with genotypes and phenotypes are documented, so co-segregation and informative meioses cannot be evaluated.
PP2	Not assessed	Not assessed: G6PD missense disease mechanism is supported, but no gene-wide benign-missense-rate assessment is available.	PMID:23006493 PMID:25201310
PP3	Not met	Not met: missense PP3 requires REVEL, but no REVEL score is available; the SpliceAI max delta 0.057 is outside this criterion's applicable path.	spliceai bayesdel
PP4	Not assessed	Not assessed: the available records lack a case-specific phenotype or family history highly specific for a single-genetic-etiology disease.	PMID:23006493 PMID:25201310
PP5	Not met	Not met: no exact-variant ClinVar expert-panel pathogenic classification exists, and the available primary evidence can be independently evaluated.	clinvar PMID:23006493
BA1	Not assessed	Not assessed: gnomAD v4.1 grpmax FAF is 12.04%, but documented G6PD deficiency effects and ancestry enrichment make a stand-alone benign call unsafe.	gnomad_v4 PMID:25201310 PMID:23006493
BS1	Not assessed	Not assessed: grpmax FAF is 12.04% versus the 1% default, but ancestry-enriched G6PD effects require a disease-specific maximum credible frequency calculation.	gnomad_v4 PMID:25201310 PMID:23006493
BS2	Not assessed	Not assessed: gnomAD reports 319 female homozygotes, but it does not verify healthy adult status or absence of G6PD deficiency in those individuals.	gnomad_v4 gnomad_v2 PMID:25201310 PMID:23006493
BS3	Not met	Not met: available testing showed approximately 40% to 80% reduced G6PD activity, not preserved function or normal splicing.	PMID:25201310 PMID:23006493
BS4	Not assessed	Not assessed: no affected relatives with genotype and phenotype data are available to demonstrate lack of segregation.
BP1	Not met	Not met: published G6PD disease cohorts emphasize missense haplotypes, including p.Val68Met, rather than a primarily truncating mechanism.	PMID:23006493 PMID:25201310
BP2	Met	Met at supporting strength: p.Val68Met was in cis with p.Asn126Asp in a pathogenic haplotype, with LOD=21.03 and D′=0.806.	PMID:23006493
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense BP4 requires REVEL, but no REVEL score is available; the SpliceAI max delta 0.057 cannot substitute for the applicable REVEL path.	spliceai bayesdel
BP5	Not assessed	Not assessed: no case is documented with this variant plus an alternate molecular basis for disease.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign or likely-benign classification provides qualifying BP6 evidence.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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.