Variant classification summary

NM_001360016.2:c.563C>T

G6PD · NP_001346945.1:p.(Ser188Phe) · NM_001360016.2

GRCh37: chrX:153762634 G>A · GRCh38: chrX:154534419 G>A

Gene: G6PD Transcript: NM_001360016.2

Final call

VUS

PS3 supporting

Variant details

Gene

G6PD

Transcript

NM_001360016.2

Protein

NP_001346945.1:p.(Ser188Phe)

gnomAD AF

0.0014093797737056851 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 Supporting: quantitative studies report reduced G6PD activity for p.Ser188Phe, including 0.64–1.1 IU/g Hb and 8% residual activity.

Final determination: Under generic ACMG/AMP 2015 fallback rules, one Supporting pathogenic criterion does not meet any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination, 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: the reviewed evidence establishes p.Ser188Phe but documents no distinct nucleotide substitution producing the same amino-acid change.	PMID:10782016 PMID:23006493 PMID:33072997
PS2	Not assessed	Not assessed: 0 documented proband-parent trios have confirmed maternity and paternity plus the required disease and family-history context.
PS3	Met	Met at supporting: G6PD Mediterranean activity was 0.64–1.1 IU/g Hb, with a separate infant showing 8% residual activity, but direct controlled variant-versus-wild-type assays were unavailable.	PMID:18568599 PMID:33072997 PMID:10782016 PMID:23006493
PS4	Not assessed	Not assessed: affected-cohort reports (29/164, 16 alleles, and 231/299) lack matched unaffected controls, so the required OR/RR >5.0 with CI excluding 1.0 cannot be calculated.	PMID:10782016 PMID:18568599 PMID:23006493 PMID:33072997
PM1	Not assessed	Not assessed: residue 188 has no approved G6PD domain entry, and the hotspot query returned no statistically significant hotspot.	cspec hotspots
PM2	Not met	Not met: gnomAD v4.1 reports AF 0.0014094 with 23 homozygotes, exceeding the PM2 threshold of 0.0001.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: one compound-heterozygous patient had 8% residual activity, but the trans c.267+5G>A variant was only described as possibly splice-altering, not confirmed pathogenic.	PMID:33072997
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: the PM5 collection contains 0 same-residue candidates, and no different pathogenic missense change at residue 188 is documented.	pm5_candidates PMID:10782016 PMID:23006493 PMID:33072997
PM6	Not assessed	Not assessed: 0 documented affected probands are described as assumed de novo without confirmed maternity and paternity.
PP1	Not assessed	Not assessed: 0 affected relatives and 0 informative meioses are documented for phenotype-consistent cosegregation.
PP2	Not assessed	Not assessed: missense disease mechanism is supported, but no qualifying low benign-missense-rate metric is available.	PMID:33072997
PP3	Not met	Not met: this missense variant requires REVEL, but no REVEL score is available for comparison with the generic PP3 thresholds.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no index-patient phenotype or family history is documented that is highly specific for G6PD deficiency with a single genetic etiology.
PP5	Not assessed	Not assessed: ClinVar has no exact-variant expert-panel classification, so ordinary laboratory and aggregate Pathogenic/Likely pathogenic labels cannot trigger PP5.	clinvar
BA1	Not met	Not met: the highest gnomAD v4.1 ancestry frequency is 4.204%, below the 5% BA1 threshold.	gnomad_v4
BS1	Not assessed	Not assessed: ancestry frequency reaches 4.204%, but disorder-specific prevalence, penetrance, and allelic-heterogeneity inputs for a credible BS1 threshold are unavailable.	gnomad_v4 gnomad_v2 PMID:10782016 PMID:23006493
BS2	Not assessed	Not assessed: gnomAD reports 23 homozygotes, but it does not establish a healthy adult hemizygote for this X-linked disorder.	gnomad_v4 gnomad_v2
BS3	Not met	Not met: available studies report reduced G6PD activity, including 0.64–1.1 IU/g Hb and 8% residual activity, rather than normal function or splicing.	PMID:18568599 PMID:33072997 PMID:10782016 PMID:23006493
BS4	Not assessed	Not assessed: 0 affected family members have documented genotype and phenotype results demonstrating lack of segregation.
BP1	Not met	Not met: most G6PD disease-causing variants are reported as missense or nonsense, not primarily truncating.	PMID:33072997
BP2	Not assessed	Not assessed: no cis pathogenic-variant observation is documented, and the reported compound-heterozygous pairing does not meet the dominant-disorder BP2 branch.
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: this missense variant requires REVEL, but no REVEL score is available for comparison with the generic BP4 thresholds.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no alternate molecular basis for the disease is documented in the case or reviewed exact-variant literature.
BP6	Not assessed	Not assessed: ClinVar has no exact-variant expert-panel Benign or Likely benign classification required to trigger BP6.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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