Variant summary: The GALT c.691C>T (p.Arg231Cys) variant involves the alteration of a conserved nucleotide and is located in the intersubunit interface of the protein (Boutron_2012). 4/4 in silico tools predict a damaging outcome for this variant. This variant has been reported multiple patients with galactosemia in homozygous or compound heterozygous state with other pathogenic variants (Alfadhel_2016, Boutron_2012, Schadewaldt_2003) and is absent in 121210 control chromosomes. A functional study showed this variant leads to loss of enzymatic activity (Coelho_2014). Another missense change (p.R231H) at this residue has also been reported in association with galactosemia (ARUP, ClinVar). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000155.4(GALT):c.691C>T (p.Arg231Cys)
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.
(7)
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
7
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.691C>T (p.Arg231Cys)
Variation ID: 25246 Accession: VCV000025246.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p13.3 9: 34648765 (GRCh38) [ NCBI UCSC ] 9: 34648762 (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 Apr 4, 2013 Sep 16, 2024 Feb 26, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000155.4:c.691C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000146.2:p.Arg231Cys missense NM_001258332.2:c.364C>T NP_001245261.1:p.Arg122Cys missense NC_000009.12:g.34648765C>T NC_000009.11:g.34648762C>T NG_009029.2:g.7177C>T NG_028966.1:g.1581C>T P07902:p.Arg231Cys - Protein change
- R122C
- Other names
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p.R231C:CGT>TGT
- Canonical SPDI
- NC_000009.12:34648764:C:T
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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.
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The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- 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 |
723 | 888 | |
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 4, 2023 | RCV000022184.19 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 26, 2024 | RCV000185919.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Sep 23, 2020 | RCV001831602.2 |
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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|---|---|---|---|---|---|
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Pathogenic
(Nov 14, 2016)
|
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: SCV000695700.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
Variant summary: The GALT c.691C>T (p.Arg231Cys) variant involves the alteration of a conserved nucleotide and is located in the intersubunit interface of the protein (Boutron_2012). … (more)
Variant summary: The GALT c.691C>T (p.Arg231Cys) variant involves the alteration of a conserved nucleotide and is located in the intersubunit interface of the protein (Boutron_2012). 4/4 in silico tools predict a damaging outcome for this variant. This variant has been reported multiple patients with galactosemia in homozygous or compound heterozygous state with other pathogenic variants (Alfadhel_2016, Boutron_2012, Schadewaldt_2003) and is absent in 121210 control chromosomes. A functional study showed this variant leads to loss of enzymatic activity (Coelho_2014). Another missense change (p.R231H) at this residue has also been reported in association with galactosemia (ARUP, ClinVar). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Jun 21, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000486527.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(May 08, 2023)
|
criteria provided, single submitter
Method: research
|
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Affected status: yes
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV003924296.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
|
|
|
Pathogenic
(Feb 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000238872.13
First in ClinVar: Jul 18, 2015 Last updated: Sep 16, 2024 |
Comment:
Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 25614870); Not observed at significant frequency in large population cohorts (gnomAD); … (more)
Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 25614870); 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: 27629047, 33636947, 36515074, 25614870, 22944367, 30718057, 25814382, 31980526, 31130284) (less)
|
|
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Pathogenic
(Feb 15, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000340775.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 4
Sex: mixed
|
|
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Pathogenic
(Aug 04, 2023)
|
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: SCV000820402.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant disrupts the p.Arg231 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7550229, 11152465, … (more)
This variant disrupts the p.Arg231 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7550229, 11152465, 22944367, 25614870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 231 of the GALT protein (p.Arg231Cys). This variant is present in population databases (rs111033749, gnomAD 0.01%). This missense change has been observed in individual(s) with low GALT enzyme activity, findings that are highly specific for galactose-1-phosphate uridylyltransferase deficiency (PMID: 14518827, 22944367; Invitae). ClinVar contains an entry for this variant (Variation ID: 25246). 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. Experimental studies have shown that this missense change affects GALT function (PMID: 25614870, 25814382). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Sep 23, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Galactosemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002085229.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
Comment:
Comment:
Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 25614870); 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: 27629047, 33636947, 36515074, 25614870, 22944367, 30718057, 25814382, 31980526, 31130284)
Comment:
This variant disrupts the p.Arg231 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7550229, 11152465, 22944367, 25614870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 231 of the GALT protein (p.Arg231Cys). This variant is present in population databases (rs111033749, gnomAD 0.01%). This missense change has been observed in individual(s) with low GALT enzyme activity, findings that are highly specific for galactose-1-phosphate uridylyltransferase deficiency (PMID: 14518827, 22944367; Invitae). ClinVar contains an entry for this variant (Variation ID: 25246). 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. Experimental studies have shown that this missense change affects GALT function (PMID: 25614870, 25814382). For these reasons, this variant has been classified as Pathogenic.
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: The GALT c.691C>T (p.Arg231Cys) variant involves the alteration of a conserved nucleotide and is located in the intersubunit interface of the protein (Boutron_2012). 4/4 in silico tools predict a damaging outcome for this variant. This variant has been reported multiple patients with galactosemia in homozygous or compound heterozygous state with other pathogenic variants (Alfadhel_2016, Boutron_2012, Schadewaldt_2003) and is absent in 121210 control chromosomes. A functional study showed this variant leads to loss of enzymatic activity (Coelho_2014). Another missense change (p.R231H) at this residue has also been reported in association with galactosemia (ARUP, ClinVar). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Comment:
Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 25614870); 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: 27629047, 33636947, 36515074, 25614870, 22944367, 30718057, 25814382, 31980526, 31130284)
Comment:
This variant disrupts the p.Arg231 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7550229, 11152465, 22944367, 25614870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 231 of the GALT protein (p.Arg231Cys). This variant is present in population databases (rs111033749, gnomAD 0.01%). This missense change has been observed in individual(s) with low GALT enzyme activity, findings that are highly specific for galactose-1-phosphate uridylyltransferase deficiency (PMID: 14518827, 22944367; Invitae). ClinVar contains an entry for this variant (Variation ID: 25246). 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. Experimental studies have shown that this missense change affects GALT function (PMID: 25614870, 25814382). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Thirteen year retrospective review of the spectrum of inborn errors of metabolism presenting in a tertiary center in Saudi Arabia. | Alfadhel M | Orphanet journal of rare diseases | 2016 | PMID: 27629047 |
| Arginine Functionally Improves Clinically Relevant Human Galactose-1-Phosphate Uridylyltransferase (GALT) Variants Expressed in a Prokaryotic Model. | Coelho AI | JIMD reports | 2015 | PMID: 25814382 |
| Functional and structural impact of the most prevalent missense mutations in classic galactosemia. | Coelho AI | Molecular genetics & genomic medicine | 2014 | PMID: 25614870 |
| Mutation spectrum in the French cohort of galactosemic patients and structural simulation of 27 novel missense variations. | Boutron A | Molecular genetics and metabolism | 2012 | PMID: 22944367 |
| Renal excretion of galactose and galactitol in patients with classical galactosaemia, obligate heterozygous parents and healthy subjects. | Schadewaldt P | Journal of inherited metabolic disease | 2003 | PMID: 14518827 |
| Relationship between genotype, activity, and galactose sensitivity in yeast expressing patient alleles of human galactose-1-phosphate uridylyltransferase. | Riehman K | The Journal of biological chemistry | 2001 | PMID: 11152465 |
| Molecular characterization of galactosemia (type 1) mutations in Japanese. | Ashino J | Human mutation | 1995 | PMID: 7550229 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GALT | - | - | - | - |
Text-mined citations for rs111033749 ...
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 Sep 29, 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.