ClinVar Genomic variation as it relates to human health
NM_000155.4(GALT):c.602G>A (p.Arg201His)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000155.4(GALT):c.602G>A (p.Arg201His)
Variation ID: 25227 Accession: VCV000025227.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9p13.3 9: 34648371 (GRCh38) [ NCBI UCSC ] 9: 34648368 (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 Apr 6, 2024 Mar 26, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000155.4:c.602G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000146.2:p.Arg201His missense NM_001258332.2:c.275G>A NP_001245261.1:p.Arg92His missense NC_000009.12:g.34648371G>A NC_000009.11:g.34648368G>A NG_009029.2:g.6783G>A NG_028966.1:g.1187G>A P07902:p.Arg201His - Protein change
- R92H
- Other names
- -
- Canonical SPDI
- NC_000009.12:34648370:G:A
-
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.
-
0.00020 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00003
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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 |
706 | 866 |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 26, 2024 | RCV000022163.22 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 17, 2022 | RCV000723397.6 | |
Pathogenic (1) |
no assertion criteria provided
|
Mar 16, 2017 | RCV001831598.2 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Dec 03, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000330954.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 7
Sex: mixed
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163241.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
|
|
Pathogenic
(Nov 09, 2021)
|
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: SCV002041495.1
First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021 |
Comment:
Variant summary: GALT c.602G>A (p.Arg201His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: GALT c.602G>A (p.Arg201His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251486 control chromosomes (gnomAD). c.602G>A has been reported in the literature in individuals affected with Galactosemia (examples: Robertson_2000, Webb_2003, Ko_2010, and Welsink-Karssies_2020). At least one publication reports experimental evidence evaluating an impact on protein function (Welsink-Karssies_2020). GALT enzyme activity in cells obtained from a homozygous individual with this variant was <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Jul 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002049032.1
First in ClinVar: Jan 05, 2022 Last updated: Jan 05, 2022 |
Comment:
The GALT c.602G>A; p.Arg201His variant (rs111033735) is reported in the literature in individuals with galactosemia (Elsas 1995), including in an individual who is homozygous for … (more)
The GALT c.602G>A; p.Arg201His variant (rs111033735) is reported in the literature in individuals with galactosemia (Elsas 1995), including in an individual who is homozygous for the variant (Welsink-Karssies 2020), as well as an individual compound heterozygous with the Duarte allele (Ko 2010). This variant is also reported in ClinVar (Variation ID: 25227). Functional studies of the variant protein have shown a mild decrease in GALT activity compared to wild type protein (Riehman 2001, Ko 2010), but GALT activity in patient erythrocytes carrying the p.Arg201His variant is more pronounced (Ko 2010, Welsink-Karssies 2020). This variant is found in the general population with a low overall allele frequency of 0.002% (7/282866 alleles) in the Genome Aggregation Database. The arginine at codon 201 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.738). Additionally, other variants at this codon (Arg201Cys, Arg201Ser) have been reported in association with galactosemia (see ClinVar Variation ID: 25226, Crespo 2020), giving further support for the importance of this codon for proper GALT function. Based on available information, the p.Arg201His variant is considered to be pathogenic. REFERENCES Crespo C et al. Molecular analysis of GALT gene in Argentinian population: Correlation with enzyme activity and characterization of a novel Duarte-like allele. Mol Genet Metab Rep. 2020 Dec 10;25:100695. PMID: 33335841. Elsas LJ et al. Galactosemia: a strategy to identify new biochemical phenotypes and molecular genotypes. Am J Hum Genet. 1995 Mar;56(3):630-9. PMID: 7887416. Ko DH et al. Molecular and biochemical characterization of the GALT gene in Korean patients with galactose-1-phosphate uridyltransferase deficiency. Clin Chim Acta. 2010 Oct 9;411(19-20):1506-10. PMID: 20547145. Riehman K et al. Relationship between genotype, activity, and galactose sensitivity in yeast expressing patient alleles of human galactose-1-phosphate uridylyltransferase. J Biol Chem. 2001 Apr 6;276(14):10634-40. PMID: 11152465. Welsink-Karssies MM et al. The Galactose Index measured in fibroblasts of GALT deficient patients distinguishes variant patients detected by newborn screening from patients with classical phenotypes. Mol Genet Metab. 2020 Mar;129(3):171-176. PMID: 31954591. (less)
|
|
Pathogenic
(Dec 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV002818187.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
|
|
Pathogenic
(Jan 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000820168.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 201 of the GALT protein (p.Arg201His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 201 of the GALT protein (p.Arg201His). This variant is present in population databases (rs111033735, gnomAD 0.02%). This missense change has been observed in individual(s) with galactose-1-phosphate uridyltransferase deficiency which is specific for Duarte or classic galactosemia (PMID: 11397328, 20547145; Invitae). ClinVar contains an entry for this variant (Variation ID: 25227). 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%. Experimental studies have shown that this missense change affects GALT function (PMID: 11152465). This variant disrupts the p.Arg201 amino acid residue in GALT. Other variant(s) that disrupt this residue have been observed in individuals with GALT-related conditions (PMID: 22461411), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Mar 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806672.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
Likely pathogenic
(Jan 04, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000796864.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
|
|
Pathogenic
(Mar 16, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Galactosemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002085220.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
The Galactose Index measured in fibroblasts of GALT deficient patients distinguishes variant patients detected by newborn screening from patients with classical phenotypes. | Welsink-Karssies MM | Molecular genetics and metabolism | 2020 | PMID: 31954591 |
Molecular basis of classic galactosemia from the structure of human galactose 1-phosphate uridylyltransferase. | McCorvie TJ | Human molecular genetics | 2016 | PMID: 27005423 |
Novel GALT variations and mutation spectrum in the Korean population with decreased galactose-1-phosphate uridyltransferase activity. | Choi R | BMC medical genetics | 2014 | PMID: 25124065 |
Correlation assessment among clinical phenotypes, expression analysis and molecular modeling of 14 novel variations in the human galactose-1-phosphate uridylyltransferase gene. | Tang M | Human mutation | 2012 | PMID: 22461411 |
Molecular and biochemical characterization of the GALT gene in Korean patients with galactose-1-phosphate uridyltransferase deficiency. | Ko DH | Clinica chimica acta; international journal of clinical chemistry | 2010 | PMID: 20547145 |
Analysis of galactosemia-linked mutations of GALT enzyme using a computational biology approach. | Facchiano A | Protein engineering, design & selection : PEDS | 2010 | PMID: 20008339 |
Verbal dyspraxia and galactosemia. | Webb AL | Pediatric research | 2003 | PMID: 12595586 |
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 |
Outcomes analysis of verbal dyspraxia in classic galactosemia. | Robertson A | Genetics in medicine : official journal of the American College of Medical Genetics | 2000 | PMID: 11397328 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GALT | - | - | - | - |
Text-mined citations for rs111033735 ...
HelpRecord last updated Apr 15, 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.