Variant summary: GALT c.221T>C (p.Leu74Pro) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251302 control chromosomes. c.221T>C has been reported in the literature in at least one individual affected with Galactosemia (Reichardt_1992). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Reichardt_1992, McCorvie_2013). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000155.4(GALT):c.221T>C (p.Leu74Pro)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Pathogenic(4); Likely pathogenic(1); Uncertain significance(1)
Pathogenic(4); Likely pathogenic(1); Uncertain significance(1)
6 out of 8 submissions contributed to this classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
8
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000155.4(GALT):c.221T>C (p.Leu74Pro)
Variation ID: 3615 Accession: VCV000003615.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p13.3 9: 34647227 (GRCh38) [ NCBI UCSC ] 9: 34647224 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Apr 13, 2025 Dec 23, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000155.4:c.221T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000146.2:p.Leu74Pro missense NM_000155.2:c.221T>C NM_001258332.2:c.19T>C NP_001245261.1:p.Cys7Arg missense NC_000009.12:g.34647227T>C NC_000009.11:g.34647224T>C NG_009029.2:g.5639T>C NG_028966.1:g.43T>C P07902:p.Leu74Pro - Protein change
- L74P, C7R
- Other names
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- Canonical SPDI
- NC_000009.12:34647226:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| GALT | Gene associated with autosomal recessive phenotype | Not yet evaluated |
GRCh38 GRCh37 |
743 | 915 | |
| LOC130001683 | - | - | - | GRCh38 | - | 119 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Conflicting classifications of pathogenicity (4) |
criteria provided, conflicting classifications
|
Dec 23, 2024 | RCV000003799.10 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 20, 2024 | RCV000723459.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
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Feb 2, 2020 | RCV001826411.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Mar 30, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000700444.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 13, 2025 |
Number of individuals with the variant: 3
Zygosity: Single Heterozygote
Sex: mixed
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Likely pathogenic
(Sep 24, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001437257.1
First in ClinVar: Oct 08, 2020 Last updated: Oct 08, 2020 |
Comment:
Variant summary: GALT c.221T>C (p.Leu74Pro) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal domain of the encoded protein sequence. … (more)
Variant summary: GALT c.221T>C (p.Leu74Pro) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251302 control chromosomes. c.221T>C has been reported in the literature in at least one individual affected with Galactosemia (Reichardt_1992). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Reichardt_1992, McCorvie_2013). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Nov 10, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003835281.2
First in ClinVar: Mar 11, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Feb 22, 2023)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226582.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PP4, PM2, PM3, PS3
Number of individuals with the variant: 1
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Pathogenic
(Jun 20, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV005079064.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Functional studies resulted in no GALT enzyme activity when L74P was over-expressed in COS cells and yeast cells (PMID: 1610789, 23583749); Not observed at significant … (more)
Functional studies resulted in no GALT enzyme activity when L74P was over-expressed in COS cells and yeast cells (PMID: 1610789, 23583749); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20008339, 1301925, 23583749, 1610789, 7887416, 23891399, 7671959, 10408771, 11261429) (less)
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Uncertain significance
(Dec 23, 2024)
C
Contributing to aggregate classification
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criteria provided, single submitter
Method: clinical testing
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Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV005835679.1
First in ClinVar: Feb 25, 2025 Last updated: Feb 25, 2025 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 74 of the GALT protein (p.Leu74Pro). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 74 of the GALT protein (p.Leu74Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with classic galactosemia (PMID: 1610789, 7887416, 30718057). ClinVar contains an entry for this variant (Variation ID: 3615). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GALT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALT function (PMID: 1610789, 23583749). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Pathogenic
(Jun 23, 1992)
N
Not contributing to aggregate classification
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no assertion criteria provided
Method: literature only
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GALACTOSEMIA I
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023964.2
First in ClinVar: Apr 04, 2013 Last updated: May 04, 2020 |
Comment on evidence:
Reichardt et al. (1992) characterized 2 galactosemia I (GALAC1; 230400) mutations, L74P and F171S (606999.0008), and 1 polymorphism, S135L, in the GALT gene. Both mutations … (more)
Reichardt et al. (1992) characterized 2 galactosemia I (GALAC1; 230400) mutations, L74P and F171S (606999.0008), and 1 polymorphism, S135L, in the GALT gene. Both mutations resulted in reduced enzymatic activity on expression studies, whereas the polymorphism resulted in near normal activity. Both mutations involved evolutionarily conserved residues, while the polymorphism occurred in a nonconserved domain. (less)
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Likely pathogenic
(Feb 02, 2020)
N
Not contributing to aggregate classification
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no assertion criteria provided
Method: clinical testing
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Galactosemia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002085186.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
Comment:
Comment:
PP3, PP4, PM2, PM3, PS3
Comment:
Functional studies resulted in no GALT enzyme activity when L74P was over-expressed in COS cells and yeast cells (PMID: 1610789, 23583749); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20008339, 1301925, 23583749, 1610789, 7887416, 23891399, 7671959, 10408771, 11261429)
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 74 of the GALT protein (p.Leu74Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with classic galactosemia (PMID: 1610789, 7887416, 30718057). ClinVar contains an entry for this variant (Variation ID: 3615). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GALT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALT function (PMID: 1610789, 23583749). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: GALT c.221T>C (p.Leu74Pro) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251302 control chromosomes. c.221T>C has been reported in the literature in at least one individual affected with Galactosemia (Reichardt_1992). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Reichardt_1992, McCorvie_2013). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
PP3, PP4, PM2, PM3, PS3
Comment:
Functional studies resulted in no GALT enzyme activity when L74P was over-expressed in COS cells and yeast cells (PMID: 1610789, 23583749); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20008339, 1301925, 23583749, 1610789, 7887416, 23891399, 7671959, 10408771, 11261429)
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 74 of the GALT protein (p.Leu74Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with classic galactosemia (PMID: 1610789, 7887416, 30718057). ClinVar contains an entry for this variant (Variation ID: 3615). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GALT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALT function (PMID: 1610789, 23583749). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The ability of an LC-MS/MS-based erythrocyte GALT enzyme assay to predict the phenotype in subjects with GALT deficiency. | Demirbas D | Molecular genetics and metabolism | 2019 | PMID: 30718057 |
| Misfolding of galactose 1-phosphate uridylyltransferase can result in type I galactosemia. | McCorvie TJ | Biochimica et biophysica acta | 2013 | PMID: 23583749 |
| Analysis of galactosemia-linked mutations of GALT enzyme using a computational biology approach. | Facchiano A | Protein engineering, design & selection : PEDS | 2010 | PMID: 20008339 |
| Galactosemia: a strategy to identify new biochemical phenotypes and molecular genotypes. | Elsas LJ | American journal of human genetics | 1995 | PMID: 7887416 |
| Molecular characterization of two galactosemia mutations and one polymorphism: implications for structure-function analysis of human galactose-1-phosphate uridyltransferase. | Reichardt JK | Biochemistry | 1992 | PMID: 1610789 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GALT | - | - | - | - |
Text-mined citations for rs111033663 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Apr 13, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.