Variant classification summary

NM_000169.3:c.644A>G

GLA · NP_000160.1:p.(Asn215Ser) · NM_000169.3

GRCh37: chrX:100653930 T>C · GRCh38: chrX:101398942 T>C

Gene: GLA Transcript: NM_000169.3

Final call

VUS

PS3 strong PM2 supporting

Variant details

Gene

GLA

Transcript

NM_000169.3

Protein

NP_000160.1:p.(Asn215Ser)

gnomAD AF

3.156636454333024e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 strong: controlled functional studies show reduced enzyme activity and abnormal N215S processing.

2

PM2 supporting: the variant is rare in gnomAD, with grpmax FAF 3.071e-05 and zero homozygotes.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion plus one supporting pathogenic criterion satisfies none of the specified pathogenic or likely pathogenic combinations, and no benign rule is satisfied; therefore the call is 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: available reports document c.644A>G p.Asn215Ser, but no pathogenic p.Asn215Ser allele from a different nucleotide change.	PMID:10666480 PMID:21972175 PMID:17555407 clinvar
PS2	Not assessed	Not assessed: Both maternity and paternity confirmation, no family history, and proband-specific de novo testing are not documented.
PS3	Met	Met (strong): three independent controlled studies show reduced or intermediate alpha-galactosidase A activity and abnormal N215S intracellular processing.	PMID:21598360 PMID:21972175 PMID:17555407
PS4	Not met	Not met: affected-family observations lack controls and do not provide the OR >5.0 with a 95% CI excluding 1.0 required for PS4.	PMID:10666480 gnomad_v4
PM1	Not assessed	Not assessed: residue 215 has no documented approved domain, critical-region, or statistically significant hotspot evidence without benign variation.	hotspots cosmic
PM2	Met	Met at supporting: gnomAD v4.1 grpmax FAF is 3.071e-05, below the PM2 threshold of 0.0001, with zero homozygotes.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: six hemizygous males and four heterozygotes were reported, but no second pathogenic allele or parent/offspring phase testing established trans configuration.	PMID:23568732 PMID:15702404
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 independently established pathogenic different missense substitution at residue 215 is documented for comparison.	pm5_candidates clinvar PMID:10666480 PMID:17555407 PMID:21972175
PM6	Not assessed	Not assessed: An assumed de novo occurrence in the proband is not documented, and parental-origin information is unavailable.
PP1	Not assessed	Not assessed: No informative affected-relative genotypes, phenotypes, or meioses are reported for evaluating co-segregation.
PP2	Not assessed	Not assessed: GLA loss of function is supported, but no validated low benign-missense rate and common-missense-mechanism assessment is supplied.	PMID:21972175 PMID:17555407
PP3	Not met	Not met: this missense variant requires REVEL, but no REVEL score is available; the SpliceAI max delta 0.002 cannot substitute for it.	spliceai bayesdel
PP4	Not assessed	Not assessed: no patient-specific phenotype or family history is provided to test the required highly specific single-etiology presentation.
PP5	Not met	Not met: exact-match ClinVar has zero expert-panel submissions, so ordinary laboratory and literature pathogenic reports cannot trigger PP5.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 3.071e-05, far below the generic BA1 threshold of 0.05.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 3.071e-05, below the generic BS1 threshold of 0.01.	gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes but provides no documented healthy adult hemizygote with age and phenotype assessment.	gnomad_v4 gnomad_v2
BS3	Not met	Not met: controlled assays show reduced or intermediate enzyme activity and abnormal N215S processing, not absence of a damaging effect.	PMID:21598360 PMID:21972175 PMID:17555407
BS4	Not assessed	Not assessed: No affected relatives lacking the variant are documented, so absence of segregation cannot be evaluated.
BP1	Not met	Not met: GLA disease literature documents numerous disease-associated missense variants, so disease is not shown to be primarily truncating.	PMID:10666480 PMID:17555407 PMID:21972175
BP2	Not assessed	Not assessed: no pathogenic variant was documented in trans or cis with c.644A>G, and the disease context is X-linked recessive rather than fully penetrant dominant.	PMID:23568732 PMID:15702404
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; the SpliceAI max delta 0.002 cannot establish BP4.	spliceai bayesdel
BP5	Not assessed	Not assessed: no case is documented with an alternate molecular basis that explains the disease instead of this variant.
BP6	Not met	Not met: exact-match ClinVar has no benign expert-panel classification, and its available assertions are non-expert Pathogenic submissions.	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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