This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 258 of the GALT protein (p.Arg258Cys). This variant is present in population databases (rs368166217, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of galactosemia (PMID: 10960497, 30718057; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 92522). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALT protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000155.4(GALT):c.772C>T (p.Arg258Cys)
Germline
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.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000155.4(GALT):c.772C>T (p.Arg258Cys)
Variation ID: 92522 Accession: VCV000092522.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p13.3 9: 34648846 (GRCh38) [ NCBI UCSC ] 9: 34648843 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jun 28, 2015 Jun 17, 2024 Mar 30, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000155.4:c.772C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000146.2:p.Arg258Cys missense NM_001258332.2:c.445C>T NP_001245261.1:p.Arg149Cys missense NC_000009.12:g.34648846C>T NC_000009.11:g.34648843C>T NG_009029.2:g.7258C>T NG_028966.1:g.1662C>T P07902:p.Arg258Cys - Protein change
- R258C, R149C
- Other names
- -
- Canonical SPDI
- NC_000009.12:34648845:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- 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 | - | - |
GRCh38 GRCh37 |
718 | 882 | |
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. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2024 | RCV000078235.28 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 9, 2023 | RCV000493672.22 |
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
(Jul 16, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000110073.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 7
Sex: mixed
|
|
|
Likely pathogenic
(Aug 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885498.1
First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018 |
|
|
|
Pathogenic
(Jan 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000931179.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 258 of the GALT protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 258 of the GALT protein (p.Arg258Cys). This variant is present in population databases (rs368166217, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of galactosemia (PMID: 10960497, 30718057; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 92522). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALT protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004198490.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jun 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000582974.7
First in ClinVar: Jul 02, 2017 Last updated: Jun 17, 2023 |
Comment:
Identified in an individual with galactosemia who harbored a second variant in the GALT gene. This individual had >5% residual enzyme activity in erythrocytes and … (more)
Identified in an individual with galactosemia who harbored a second variant in the GALT gene. This individual had >5% residual enzyme activity in erythrocytes and a Duarte-like isoelectric focusing banding pattern (Berry et al., 2000); Considered a milder GALT variant (Korner et al., 2019); 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: 25087612, 30718057, 15633893, 30808388, 31194895, 10408771, 20008339, 23690308, 10960497, 17876724, 29350350, 11261429, 10384398, 31194252, 34426522, 35677809) (less)
|
|
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Likely pathogenic
(Mar 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226597.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PP4, PM2, PM3, PS4_moderate
Number of individuals with the variant: 2
|
|
|
Likely pathogenic
(Mar 13, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000800530.2
First in ClinVar: Jun 28, 2015 Last updated: Dec 23, 2019 |
|
|
|
Likely pathogenic
(Oct 11, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001469241.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
|
|
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Uncertain significance
(Apr 09, 2021)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003808590.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
Identified in an individual with galactosemia who harbored a second variant in the GALT gene. This individual had >5% residual enzyme activity in erythrocytes and a Duarte-like isoelectric focusing banding pattern (Berry et al., 2000); Considered a milder GALT variant (Korner et al., 2019); 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: 25087612, 30718057, 15633893, 30808388, 31194895, 10408771, 20008339, 23690308, 10960497, 17876724, 29350350, 11261429, 10384398, 31194252, 34426522, 35677809)
Comment:
PP3, PP4, PM2, PM3, PS4_moderate
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:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 258 of the GALT protein (p.Arg258Cys). This variant is present in population databases (rs368166217, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of galactosemia (PMID: 10960497, 30718057; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 92522). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALT protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
Identified in an individual with galactosemia who harbored a second variant in the GALT gene. This individual had >5% residual enzyme activity in erythrocytes and a Duarte-like isoelectric focusing banding pattern (Berry et al., 2000); Considered a milder GALT variant (Korner et al., 2019); 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: 25087612, 30718057, 15633893, 30808388, 31194895, 10408771, 20008339, 23690308, 10960497, 17876724, 29350350, 11261429, 10384398, 31194252, 34426522, 35677809)
Comment:
PP3, PP4, PM2, PM3, PS4_moderate
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Translating principles of precision medicine into speech-language pathology: Clinical trial of a proactive speech and language intervention for infants with classic galactosemia. | Peter B | HGG advances | 2022 | PMID: 35677809 |
| Pathophysiology and management of classic galactosemic primary ovarian insufficiency. | Hagen-Lillevik S | Reproduction & fertility | 2021 | PMID: 35118398 |
| Abnormal N-glycan fucosylation, galactosylation, and sialylation of IgG in adults with classical galactosemia, influence of dietary galactose intake. | Treacy EP | JIMD reports | 2021 | PMID: 34485021 |
| Heterogeneity of disease-causing variants in the Swedish galactosemia population: Identification of 16 novel GALT variants. | Ohlsson A | Journal of inherited metabolic disease | 2019 | PMID: 31194895 |
| Deficits of facial emotion recognition and visual information processing in adult patients with classical galactosemia. | Korner M | Orphanet journal of rare diseases | 2019 | PMID: 30808388 |
| 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 |
| Galactose-1-Phosphate Uridyltransferase Activities in Different Genotypes: A Retrospective Analysis of 927 Samples. | Yuzyuk T | The journal of applied laboratory medicine | 2018 | PMID: 33636947 |
| Biochemical changes and clinical outcomes in 34 patients with classic galactosemia. | Yuzyuk T | Journal of inherited metabolic disease | 2018 | PMID: 29350350 |
| Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. | Tabor HK | American journal of human genetics | 2014 | PMID: 25087612 |
| Modifiers of ovarian function in girls and women with classic galactosemia. | Spencer JB | The Journal of clinical endocrinology and metabolism | 2013 | PMID: 23690308 |
| Analysis of galactosemia-linked mutations of GALT enzyme using a computational biology approach. | Facchiano A | Protein engineering, design & selection : PEDS | 2010 | PMID: 20008339 |
| Combination of enzyme analysis, allele-specific PCR and sequencing to detect mutations in the GALT gene. | Calderon FR | Journal of inherited metabolic disease | 2007 | PMID: 17876724 |
| Molecular and biochemical basis for variants and deficiency of GALT: report of 4 novel mutations. | Shin YS | Bratislavske lekarske listy | 2004 | PMID: 15633893 |
| Galactose breath testing distinguishes variant and severe galactose-1-phosphate uridyltransferase genotypes. | Berry GT | Pediatric research | 2000 | PMID: 10960497 |
| Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. | Tyfield L | Human mutation | 1999 | PMID: 10408771 |
| Molecular and biochemical basis for variants and deficiency forms of galactose-1-phosphate uridyltransferase. | Shin YS | Journal of inherited metabolic disease | 1999 | PMID: 10384398 |
| The molecular biology of galactosemia. | Elsas LJ 2nd | Genetics in medicine : official journal of the American College of Medical Genetics | 1998 | PMID: 11261429 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GALT | - | - | - | - |
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Text-mined citations for rs368166217 ...
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 Oct 27, 2024
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.