Variant classification summary

NM_000155.4:c.563A>G

GALT · NP_000146.2:p.(Gln188Arg) · NM_000155.4

GRCh37: chr9:34648167 A>G · GRCh38: chr9:34648170 A>G

Gene: GALT Transcript: NM_000155.4

Final call

VUS

PS3 supporting PM1 moderate PP3 supporting

Variant details

Gene

GALT

Transcript

NM_000155.4

Protein

NP_000146.2:p.(Gln188Arg)

gnomAD AF

0.0025412472555520864 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: Q188R GALT activity was 0–0.75% of control in approved model assays.

2

PM1 moderate: p.Gln188Arg lies within the active-site interval Phe171–Gln188.

3

PP3 supporting: REVEL 0.975 exceeds the VCEP missense threshold of 0.7.

Final determination: Under the GALT VCEP Version 1.1 ACMG/AMP 2015-based framework, PS3 supporting plus PM1 moderate plus PP3 supporting satisfies neither a pathogenic nor a benign rule, so the classification 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: c.563A>G is a missense substitution, while the GALT VCEP PVS1 tree names only nonsense/frameshift, splice-site, deletion, duplication, and initiation-codon pathways.	cspec vcep_galt_pvs1_decisiontree pvs1_variant_assessment
PS1	Not met	Not met: no distinct previously established pathogenic missense variant producing p.Gln188Arg was identified beyond the observed c.563A>G variant.	cspec clinvar PMID:16838075
PS2	N/A	Not applicable: the GALT VCEP explicitly designates PS2 as not applicable and directs de novo evidence to PM6.	cspec
PS3	Met	Met at Supporting: Q188R activity was 0–0.75% of control in approved E. coli and yeast model assays, below the VCEP's up-to-20% PS3 threshold.	cspec vcep_ps3_functional_assay_galt_final_for_clin_gen_updated_july_2024
PS4	N/A	Not applicable: the GALT VCEP explicitly designates PS4 as not applicable, regardless of the literature packet's case-observation leads.	cspec
PM1	Met	Met at moderate strength: p.Gln188Arg alters residue 188, within the VCEP-defined active-site interval Phe171–Gln188.	cspec
PM2	Not met	Not met: gnomAD v4.1 PopMax FAF is 0.00311645, above the VCEP PM2 cutoff of 0.0005 (0.05%), and the variant is on the PM2 exception list.	cspec gnomad_v4 gnomad_v2 vcep_galt_pm2_exceptions_list
PM3	Not met	Not met: PM2 is required, but the VCEP exception list excludes Q188R and gnomAD v4.1 reports PopMax FAF 0.00311645 versus the 0.0005 PM2 threshold.	cspec vcep_galt_pm2_exceptions_list gnomad_v4
PM4	N/A	Not applicable: p.Gln188Arg is a missense substitution with no protein-length change, whereas PM4 covers only non-repeat in-frame indels or stop-loss variants.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: no qualifying alternate missense comparator at residue 188 was available, and the comparator search recorded an HTTP 429 retrieval error.	cspec pm5_candidates
PM6	Not assessed	Not assessed: confirmed paternity and maternity plus PP4 are required, but parental testing and qualifying PP4 evidence are not documented.	cspec
PP1	Not assessed	Not assessed: no affected or unaffected segregations or likelihood calculation is documented against the VCEP's 4:1, 16:1, or 32:1 thresholds.	cspec
PP2	N/A	Not applicable: the GALT VCEP states that GALT is not constrained for missense variants, with a Z score of 0.91.	cspec
PP3	Met	Met: REVEL score 0.975 meets the GALT VCEP PP3 missense threshold of >=0.7.	cspec revel
PP4	Not assessed	Not assessed: the VCEP requires RBC GALT activity <10%, but no patient-specific enzyme activity or confirmatory phenotype result is available.	cspec PMID:16838075
PP5	N/A	Not applicable: the GALT VCEP states that PP5 is not for use under the VCEP Review Committee recommendation.	cspec
BA1	Not met	Not met: gnomAD v4.1 PopMax FAF is 0.00311645 (0.311645%), below the VCEP's BA1 threshold of 0.01 (1%).	cspec gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD v4.1 PopMax FAF is 0.00311645 (0.311645%), below the VCEP's BS1 threshold of 0.005 (0.5%).	cspec gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: gnomAD reports 3 homozygotes in v4.1, but no individual is confirmed unaffected by GALT activity levels as required by the VCEP.	cspec gnomad_v4 gnomad_v2
BS3	Not met	Not met: Q188R activity was 0–0.75% in approved model assays, far below the VCEP BS3 Supporting requirement of greater than 50% enzyme activity.	cspec vcep_ps3_functional_assay_galt_final_for_clin_gen_updated_july_2024
BS4	Not assessed	Not assessed: no unaffected individual with RBC GALT activity ≥25% and no bone marrow transfusion is documented.	cspec
BP1	N/A	Not applicable: the GALT VCEP states that BP1 does not apply because missense variants are also known to cause disease.	cspec
BP2	Not assessed	Not assessed: no cis/trans phase, unaffected carrier-range enzyme result, or full GALT sequencing including the promoter region is documented.	cspec
BP3	N/A	Not applicable: the GALT VCEP explicitly marks BP3 as not applicable, so repeat-region context cannot activate this criterion.	cspec
BP4	Not met	Not met: REVEL score 0.975 is above, rather than below, the GALT VCEP BP4 missense threshold of <0.15.	cspec revel
BP5	N/A	Not applicable: the GALT VCEP designates BP5 as not applicable because galactosemia has variable onset and expressivity.	cspec
BP6	N/A	Not applicable: the GALT VCEP states that BP6 is not for use under the VCEP Review Committee recommendation.	cspec
BP7	N/A	Not applicable: the variant is missense, whereas the GALT VCEP BP7 rule names silent and qualifying intronic variants.	cspec

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