The GALT NM_000155.4:c.563A>G (NP_000146.2:p.(Gln188Arg)) missense variant has previously been reported in somatic cancers (COSMIC; COSV108227022, n = 1 time). Experimental evidence: 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. Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.GALT produces an enzyme that helps the body break down galactose, a sugar found in milk, into forms the body can use. Loss of GALT activity causes classic galactosemia, an inherited metabolic disorder that can be life-threatening in newborns if lactose is not removed from the diet. GALT has no established direct role in cancer.
The recorded framework is ClinGen GALT VCEP v1.1. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
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.
Met at moderate strength: p.Gln188Arg alters residue 188, within the VCEP-defined active-site interval Phe171–Gln188.
Met: REVEL score 0.975 meets the GALT VCEP PP3 missense threshold of >=0.7.
No benign criterion marked as applied in the recorded assessment.
VUS: PS3 (supporting), PM1 (moderate), and PP3 (supporting) do not satisfy a GALT VCEP pathogenic or benign combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 4,102 / 1,614,168 alleles. Recorded AF 0.00254125. Recorded homozygote count 3.
This variant is present in gnomAD v2.1 (AF= 0.00145665; MAF= 0.14567%, 412/282840 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00266291; MAF= 0.26629%, 344/129182 alleles, homozygotes = 1); grpmax FAF= 0.00241661.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.975. Refer to the recorded PP3/BP4 rationale for interpretation.
38 Pathogenic · 2 Uncertain significance. ClinVar API review status: criteria provided, conflicting classifications.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV108227022, n = 1 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under ClinGen GALT VCEP v1.1, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 7 not met · 7 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1 is not applicable because the variant is missense and the GALT VCEP PVS1 decision tree provides no missense pathway.
PM4 is not applicable because the missense substitution does not produce a protein-length change and is neither an in-frame indel nor a stop-loss variant under the VCEP rule.
BP3 is explicitly not applicable under the GALT VCEP CSPEC.
No segregation, non-segregation, or confirmed de novo parental-testing evidence is available to apply PM6, PP1, or BS4; PS2 is not applicable under the GALT VCEP specification.
Only the ClinGen GALT VCEP Version 1.1 rules were applied.
PS4, PP5, BP5, and BP6 are explicitly not applicable under this VCEP.
PP4 remains not assessed because the required patient-specific RBC GALT enzyme activity and confirmatory testing are not available.
PP3 is met at Supporting strength from the VCEP-named REVEL missense path; BP4 is not met because the same REVEL score is above the benign cutoff; BP7 is not applicable to this missense variant.
No criteria match.
NM_000155.4:c.563A>G (p.Gln188Arg/Q188R) shows severe loss of GALT function in approved, non-patient model-system assays. The VCEP functional-assay table reports Q188R at 0.75% activity in E. coli, 0% activity in E. coli in an independent assay, 0% activity in yeast, 0.025% activity in a separate yeast assay, and 0% activity in a yeast assay summarized in the final variant table. These quantitative results are far below the VCEP's PS3 Supporting limit of up to 20% enzyme activity. The assays used recombinant or engineered GALT in E. coli or yeast, with wild-type GALT and/or empty-vector/null controls where reported; the table marks the relevant assays as approved and assigns PS3 Supporting. The assay table does not report formal pathogenic/likely pathogenic or benign/likely benign validation-control counts for these studies, and some replicate descriptions are incomplete, so the evidence is not upgraded beyond the VCEP-specified Supporting level.
Applicable for up to 20% enzyme activity in a model system
The variant encodes p.Gln188Arg, placing the altered residue at amino-acid position 188. The GALT VCEP defines its PM1 active-site interval as Phe171 through Gln188; position 188 is included at the interval endpoint. No separate hotspot route is needed.
PM1 applied at moderate strength for variants that occur in the active site from Phe171 to Gln188
The variant is a missense variant, NM_000155.4:c.563A>G (p.Gln188Arg). The GALT VCEP specifies REVEL for missense variants and requires a score >=0.7 for PP3. The recorded REVEL score is 0.975, meeting that threshold. SpliceAI is not used for PP3 here because the VCEP's SpliceAI path is specifically for non-canonical splicing variants, not this missense situation; the same prediction is therefore not double-counted across criteria.
* For missense variants use REVEL with a score ≥0.7
The variant is a missense p.Gln188Arg change and is documented in ClinVar and the reviewed literature, but the available evidence identifies only the same c.563A>G nucleotide change. No distinct previously established pathogenic missense variant producing the same amino-acid change was identified, and the VCEP requires an additional variant curated under its specifications without using PS1. Therefore PS1 is not met.
PS1 will be applied at the strong level for 1 previously established pathogenic missense variant or use Table 2 in Walker et al., PMID: 37352859 for splicing variant ... The other variant(s) used for evidence should also have been curated using GALT VCEP rule specifications and reach a pathogenic/likely pathogenic classification without using PS1.
The GALT VCEP permits PM2 only at supporting strength when the gnomAD PopMax FAF is ≤0.0005 (0.05%). The governing default population source is used because the PM2 rule specifies gnomAD PopMax FAF but does not specify a non-cancer or exome-only subset. The gnomAD v4.1 all-comers PopMax FAF is 0.00311645 and the gnomAD v2.1 all-comers PopMax FAF is 0.00241661, both above 0.0005. The VCEP PM2 exception list also identifies NM_000155.4(GALT):c.563A>G (p.Gln188Arg) as a known pathogenic variant that does not meet PM2. Therefore PM2 is not met.
* Can only be used at the supporting level * Use the PopMax filtering allele frequency (FAF) from gnomAD. * Use if variant is present at ≤ 0.0005 or 0.05% * One order of magnitude below BS1 * PM2 is not considered conflicting data with BP4 or BP7 * A curated list of _GALT_ variants known to be pathogenic despite not fulfilling the PM2 criterion has been developed (see PM2 exception list)
PM3 is not met under the GALT VCEP rule because the variant does not meet the required PM2 prerequisite: the VCEP PM2 exception list specifically identifies NM_000155.4(GALT):c.563A>G (p.Gln188Arg) as a known pathogenic variant that does not meet PM2, and gnomAD v4.1 reports a PopMax FAF of 0.00311645, above the VCEP PM2 threshold of 0.0005. In addition, the available evidence does not document an affected individual with this variant in trans with a pathogenic variant, phase, or VCEP-defined PP4 fulfillment; therefore no PM3 points can be established and no PM3 strength can be assigned.
Variant under investigation meets PM2, identified individual(s) meet PP4, and at least 1 PM3 point has been reached.
The GALT VCEP specifies BA1 at stand-alone strength when the gnomAD PopMax FAF is at least 0.01 (1%). The governing default population source is used because this rule does not specify a non-cancer or exome-only subset. In gnomAD v4.1 all-comers, the PopMax FAF is 0.00311645 (0.311645%), below 0.01; gnomAD v2.1 all-comers also has a PopMax FAF of 0.00241661 (0.241661%), below 0.01. Therefore BA1 is not met.
Use a minor allele frequency cutoff of ≥0.01 (1%) (use PopMax FAF in gnomAD). This frequency was calculated using the Whiffen-Ware calculator with a prevalence estimated at 1 in 10,000, penetrance at 100%, maximum allelic contribution and maximum genetic contribution at 100%.
The GALT VCEP specifies BS1 at strong strength when the gnomAD PopMax FAF is at least 0.005 (0.5%). The governing default population source is used because this rule does not specify a non-cancer or exome-only subset. The gnomAD v4.1 all-comers PopMax FAF is 0.00311645 (0.311645%), and the gnomAD v2.1 all-comers PopMax FAF is 0.00241661 (0.241661%); both are below 0.005. Therefore BS1 is not met.
Use a minor allele frequency cutoff of ≥0.005 (0.5%) (use PopMax FAF in gnomAD). This frequency was calculated using the Whiffen-Ware calculator with a prevalence estimated at 1 in 10,000, penetrance at 100%, maximum allelic contribution of 50% and maximum genetic contribution at 100%.
BS3 Supporting requires a functional assay in non-patient material showing greater than 50% enzyme activity in a model system. The VCEP functional-assay table instead reports Q188R activity at 0.75% or less in the E. coli assays and approximately 0–0.2% in the yeast assays, with the final variant table assigning Q188R to PS3 Supporting rather than BS3 Supporting. Therefore the available functional evidence does not meet the BS3 threshold and directly supports abnormal, not normal, GALT function.
* Can only be used at the supporting level * Functional assay in non-patient material * BS3\_Supporting is applicable for greater than 50% enzyme activity in a model system (cannot apply at strong level)
The variant is a missense variant, so the applicable GALT VCEP BP4 path is REVEL with a score <0.15. The recorded REVEL score is 0.975, which does not meet the benign threshold. The VCEP's SpliceAI BP4 path applies to non-canonical splicing variants, not this missense situation, so the SpliceAI max delta score of 0.359 is not used for BP4.
* For missense variants use REVEL with a score of \<0.15 * In-frame in/dels, Provean (“neutral”) and MutationTaster (“polymorphism”) must agree For non-canonical splicing variants use SpliceAI with a score of \<0.1, do not use if there is evidence of a cryptic splice site
The available PM5 candidate collection found no same-residue comparator variants at GALT residue 188, but the collection also records an HTTP 429 retrieval error. Because PM5 requires a qualifying pathogenic or likely pathogenic alternate missense change at the residue, with no benign variation, VCEP curation without PM5, and Grantham comparison, the criterion cannot be conclusively evaluated from the available evidence.
Splicing abnormalities (using VCEP-specified prediction algorithms or evidence from literature) should be excluded for all missense variants ... PM5 will be applied at moderate strength for 1 pathogenic variant with no benign variation at the residue ... The other variant(s) used for evidence should also have been curated using the GALT VCEP rule specifications and must reach a pathogenic/likely pathogenic classification without PM5. ... Grantham should be used to compare the variants. The new variant must be equal or worse than the known pathogenic variant.
The VCEP requires confirmed paternity and maternity and that the patient meet PP4. The available case evidence does not document parental identity testing, parental variant results, or the PP4 requirements for this patient, so PM6 cannot be evaluated.
Paternity and maternity must be confirmed. Patient must meet PP4. ... Because there has only ever been one reported de novo occurrence of a _GALT_ variant and de novo occurrence is not expected to significantly contribute to disease, the VCEP will use PM6 and not PS2. PM6 will not be upgraded with number of occurrences.
The VCEP requires sufficient affected and unaffected segregations to reach a likelihood of 4:1 for PP1 Supporting, 16:1 for PP1 Moderate, or 32:1 for PP1 Strong. The available case evidence contains no documented affected or unaffected family segregations, meioses, or likelihood calculation, so PP1 cannot be assessed.
Using general recommendations from Oza AM et al., 2018, (PMID: 30311386), sufficient affected and unaffected segregations have been counted to reach likelihood of 4:1.
The VCEP requires RBC GALT enzyme activity below 10% and confirmatory testing for PP4 at supporting strength. The available case evidence does not report the patient's RBC GALT enzyme activity or confirmatory phenotype testing, so PP4 cannot be evaluated. The review of p.Q188R describes severe phenotype associations in historical cohorts but is not a case-specific enzyme result.
* RBC GALT enzyme activity <10% * In order to apply PP4 at the supporting level, newborn screen alone would not count, must have confirmatory testing.
The GALT VCEP requires an individual confirmed to be unaffected by GALT activity levels for BS2. The available population data show one homozygote in gnomAD v2.1 and three homozygotes in gnomAD v4.1, but they do not establish that any carrier or homozygote was clinically confirmed unaffected by GALT activity levels. The required unaffected-status evidence is therefore unavailable, so BS2 is not assessed.
This code is applicable when individual is confirmed to be unaffected by GALT activity levels
The VCEP requires an individual considered unaffected to have RBC GALT enzyme activity of at least 25%, with no bone marrow transfusions. The available case evidence documents no unaffected tested relative or qualifying RBC GALT activity and transfusion history, so BS4 cannot be assessed.
Individual considered unaffected RBC GALT enzyme activity ≥25% with the caveat of no bone marrow transfusions in individual.
BP2 cannot be assessed from the available evidence. The VCEP requires either observation of the investigated variant in cis with a likely pathogenic or pathogenic variant, or observation in trans with a pathogenic variant in an unaffected individual whose RBC GALT enzyme activity is in the carrier range; it also requires full GALT gene sequencing including the promoter region. The evidence provided does not establish cis or trans phase, an unaffected carrier-range individual, or completion of the required full-gene-plus-promoter sequencing.
* Observed in cis with a likely pathogenic or pathogenic variant OR observed in trans with a pathogenic variant in an unaffected individual with RBC GALT enzyme activity in the carrier range...* Pathogenicity of first variant must be determined using VCEP guidelines. ...* Full gene sequencing including promoter region must have been completed to apply BP2
NM_000155.4:c.563A>G is a missense variant, NP_000146.2:p.(Gln188Arg), in exon 6. The governing GALT VCEP PVS1 specification directs use of its attached decision tree, whose named entry pathways are nonsense/frameshift, GT--AG 1,2 splice sites, deletion, duplication, and initiation codon. Because this missense substitution is outside every named PVS1 variant class, PVS1 is not applicable; exon 6 being in-frame does not create a missense PVS1 pathway.
* The Galactosemia VCEP will utilize SVI’s PVS1 recommendation for determining applicable PVS1 strength level (Abou Tayoun et al 2018; PMID: 30192042). Refer to the modified PVS1 decision tree attached. * Exons 6, 7, and 9 are in-frame. Exon skipping consequences for splice site variants are listed in the attachment as well. ... **Nonsense or Frameshift** ... **GT--AG** **1,2 splice** **sites** ... **Deletion** ... **Duplication** ... **Initiation Codon**
The GALT VCEP explicitly marks PS2 as not applicable and directs evaluators to use PM6 rather than PS2 for de novo evidence.
Not Applicable
The GALT VCEP marks PS4 as not applicable. The literature packet lists case-observation leads for PMIDs 10439960, 10649501, 1897530, and 21188552, but no verified case-control counts, control comparison, odds ratio, or confidence interval is available in the selectively read evidence; this cannot override the VCEP applicability designation.
Not applicable
NM_000155.4:c.563A>G is a missense substitution, NP_000146.2:p.(Gln188Arg), and does not change protein length. The GALT VCEP PM4 rule is limited to protein-length changes due to in-frame deletions or insertions in a non-repeat region, or to stop-loss variants. Neither condition applies.
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
The GALT VCEP marks PP2 not applicable and states that GALT is not constrained for missense variants, with a missense Z score of 0.91.
GALT is not constrained for missense (Z score: 0.91) variants.
The GALT VCEP designates PP5 as not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The literature packet's PP5 lead therefore cannot be used.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The GALT VCEP marks BP1 not applicable because missense variants are also known to cause disease; this missense variant therefore lies outside BP1's applicable scope.
Not applicable; missense variants are also known to cause disease.
The GALT VCEP CSPEC explicitly marks BP3 as not applicable. BP3 is therefore not evaluated for this variant, regardless of repeat-region context.
Not Applicable
The GALT VCEP marks BP5 as not applicable because galactosemia has variable age of onset and variable expressivity in affected individuals. No alternate molecular basis evidence can change that VCEP applicability designation.
Galactosemia has variable age of onset and there is variable expressivity in affected individuals.
The GALT VCEP designates BP6 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. No benign reputable-source assertion can be applied under this VCEP.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The variant is missense (p.Gln188Arg), not a silent variant or an intronic variant at or beyond the positions named by the GALT VCEP BP7 rule. It is therefore outside BP7's governing scope. The separate BP4 prerequisite is also not satisfied, but BP7 is not_applicable upstream because the variant type is outside the rule's named scope.
* Use “as is”, but no conservation requirement * BP4 must be applied for BP7 to be used, the codes can be combined * Do not use for silent variants in the first nucleotide or last 3 nucleotides of the exon * Can also be used for intronic variants at or beyond positions +7/-21 with no predicted effect on splicing.
Every interpreted variant in GALT, mapped onto the exon structure of NM_000155.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Amish5 / 912 | 0.0055 |
| European (non-Finnish)3779 / 1,180,028 | 0.00323 hom |
| Remaining individuals151 / 62,508 | 0.0024 |
| Admixed American54 / 60,016 | 0.0009 |
| African/African American51 / 75,050 | 0.00068 |
| South Asian51 / 91,084 | 0.00056 |
| Middle Eastern1 / 6,052 | 0.00017 |
| European (Finnish)9 / 64,022 | 0.00014 |
| Ashkenazi Jewish1 / 29,606 | 3.4e-05 |
| European (non-Finnish)344 / 129,182 | 0.00271 hom |
| Remaining individuals8 / 7,222 | 0.0011 |
| Admixed American28 / 35,436 | 0.00079 |
| African/African American18 / 24,964 | 0.00072 |
| South Asian13 / 30,616 | 0.00042 |
| European (Finnish)1 / 25,096 | 4e-05 |
This variant is present in gnomAD v4.1 (AF= 0.00254125; MAF= 0.25412%, 4102/1614168 alleles, homozygotes = 3) and has highest observed frequency in the Amish population (AF= 0.00548246; MAF= 0.54825%, 5/912 alleles, homozygotes = 0); grpmax FAF= 0.00311645.
This variant is present in gnomAD v2.1 (AF= 0.00145665; MAF= 0.14567%, 412/282840 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00266291; MAF= 0.26629%, 344/129182 alleles, homozygotes = 1); grpmax FAF= 0.00241661.
Not available in gnomAD-Canada v1.0.
The variant is a missense variant, NM_000155.4:c.563A>G (p.Gln188Arg). The GALT VCEP specifies REVEL for missense variants and requires a score >=0.7 for PP3. The recorded REVEL score is 0.975, meeting that threshold. SpliceAI is not used for PP3 here because the VCEP's SpliceAI path is specifically for non-canonical splicing variants, not this missense situation; the same prediction is therefore not double-counted across criteria.
* For missense variants use REVEL with a score ≥0.7
The variant is a missense variant, so the applicable GALT VCEP BP4 path is REVEL with a score <0.15. The recorded REVEL score is 0.975, which does not meet the benign threshold. The VCEP's SpliceAI BP4 path applies to non-canonical splicing variants, not this missense situation, so the SpliceAI max delta score of 0.359 is not used for BP4.
* For missense variants use REVEL with a score of \<0.15 * In-frame in/dels, Provean (“neutral”) and MutationTaster (“polymorphism”) must agree For non-canonical splicing variants use SpliceAI with a score of \<0.1, do not use if there is evidence of a cryptic splice site
The variant is missense (p.Gln188Arg), not a silent variant or an intronic variant at or beyond the positions named by the GALT VCEP BP7 rule. It is therefore outside BP7's governing scope. The separate BP4 prerequisite is also not satisfied, but BP7 is not_applicable upstream because the variant type is outside the rule's named scope.
* Use “as is”, but no conservation requirement * BP4 must be applied for BP7 to be used, the codes can be combined * Do not use for silent variants in the first nucleotide or last 3 nucleotides of the exon * Can also be used for intronic variants at or beyond positions +7/-21 with no predicted effect on splicing.
SpliceAI predicts possible splice impact for this variant (max delta score = 0.36). REVEL score = 0.975. BayesDel score = 0.57417.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
"Recent data suggest a clear genotype–phenotype relationship. p.Q188R is associated with a severe biochemical and clinical genotype, with nearly undetectable residual erythrocyte GALT activity in homozygotes (Tyfield et al 1999)"
Molecular biology, p. 517; Variables associated with long-term complications, p. 520; Galactose tolerance, p. 522
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.00254125; MAF= 0.25412%, 4102/1614168 alleles, homozygotes = 3) and has highest observed frequency in the Amish population (AF= 0.00548246; MAF= 0.54825%, 5/912 alleles, homozygotes = 0); grpmax FAF= 0.00311645.
This variant is present in gnomAD v2.1 (AF= 0.00145665; MAF= 0.14567%, 412/282840 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00266291; MAF= 0.26629%, 344/129182 alleles, homozygotes = 1); grpmax FAF= 0.00241661.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (38 clinical laboratories) and as Uncertain significance (2 clinical laboratories). (ClinVarID = 3614)
SpliceAI predicts possible splice impact for this variant (max delta score = 0.36). REVEL score = 0.975. BayesDel score = 0.57417.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV108227022, n = 1 times).
This variant does not lie in a statistically significant hotspot.