ClinVar Genomic variation as it relates to human health
NM_000155.4(GALT):c.692G>A (p.Arg231His)
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
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NM_000155.4(GALT):c.692G>A (p.Arg231His)
Variation ID: 25247 Accession: VCV000025247.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9p13.3 9: 34648766 (GRCh38) [ NCBI UCSC ] 9: 34648763 (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 Oct 8, 2024 Oct 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000155.4:c.692G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000146.2:p.Arg231His missense NM_001258332.2:c.365G>A NP_001245261.1:p.Arg122His missense NC_000009.12:g.34648766G>A NC_000009.11:g.34648763G>A NG_009029.2:g.7178G>A NG_028966.1:g.1582G>A P07902:p.Arg231His - Protein change
- R122H
- Other names
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- Canonical SPDI
- NC_000009.12:34648765:G:A
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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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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GALT | - | - |
GRCh38 GRCh37 |
717 | 881 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 17, 2023 | RCV000022185.15 | |
Pathogenic (1) |
no assertion criteria provided
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Aug 29, 2017 | RCV001826498.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 13, 2021 | RCV002254268.6 | |
GALT-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Aug 28, 2024 | RCV004752719.1 |
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
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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
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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
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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
(Oct 17, 2023)
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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:
unknown
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Baylor Genetics
Accession: SCV004198501.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Nov 03, 2021)
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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:
unknown
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Myriad Genetics, Inc.
Accession: SCV002060145.2
First in ClinVar: Jan 15, 2022 Last updated: Dec 24, 2022 |
Comment:
NM_000155.3(GALT):c.692G>A(R231H) is a missense variant classified as likely pathogenic in the context of galactosemia. R231H has been observed in cases with relevant disease (PMID: 7550229, … (more)
NM_000155.3(GALT):c.692G>A(R231H) is a missense variant classified as likely pathogenic in the context of galactosemia. R231H has been observed in cases with relevant disease (PMID: 7550229, 22944367, 23924834, 27176039). Functional assessments of this variant are available in the literature (PMID: 11152465, 25614870). R231H has been observed in population frequency databases (gnomAD: OTH 0.02%). In summary, NM_000155.3(GALT):c.692G>A(R231H) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. (less)
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Pathogenic
(Sep 23, 2021)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001983411.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
Variant summary: GALT c.692G>A (p.Arg231His) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, C-terminal domain (IPR005850) of the encoded protein … (more)
Variant summary: GALT c.692G>A (p.Arg231His) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, C-terminal domain (IPR005850) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250550 control chromosomes (gnomAD). c.692G>A has been reported in the literature in multiple individuals affected with Galactosemia, including one homozygote (Ashino_1995, Ozgul_2013). These data indicate that the variant is very likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and this variant results in absent GALT enzyme activity (Ashino_1995, Hirokawa_1999, Riehman_2001, Coelho_2014). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 13, 2021)
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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: SCV002525790.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
PP3, PP4, PM2, PM5, PS3, PS4
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Pathogenic
(Oct 03, 2023)
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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: SCV000826865.4
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 231 of the GALT protein (p.Arg231His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 231 of the GALT protein (p.Arg231His). This variant is present in population databases (rs111033754, gnomAD no frequency). This missense change has been observed in individual(s) with Galactose-1-phosphate uridylyltransferase deficiency (PMID: 7550229, 22944367, 27176039). ClinVar contains an entry for this variant (Variation ID: 25247). 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: 7550229, 11152465, 25614870). 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: 14518827, 22944367, 25614870, 25814382). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 29, 2017)
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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: SCV002085230.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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Pathogenic
(Aug 28, 2024)
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no assertion criteria provided
Method: clinical testing
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GALT-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005365554.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The GALT c.692G>A variant is predicted to result in the amino acid substitution p.Arg231His. This variant has been reported in the homozygous or compound heterozygous … (more)
The GALT c.692G>A variant is predicted to result in the amino acid substitution p.Arg231His. This variant has been reported in the homozygous or compound heterozygous state in patients with galactosemia, several of whom were reported to have absent GALT enzyme activity in erythrocytes (Ashino et al. 1995. PubMed ID: 7550229; Boutron et al. 2012. PubMed ID: 22944367; Garcia et al. 2016. PubMed ID: 27176039; Yuzyuk et al. 2018. PubMed ID: 30172461). The p.Arg231His substitution has been reported to reduce protein expression and enzyme activity in functional studies (Ashino et al. 1995. PubMed ID: 7550229; Riehman et al. 2001. PubMed ID: 11152465; Coelho et al. 2014. PubMed ID: 25614870). The p.Arg231 amino acid residue is located at the intersubunit interface and has been predicted to disrupt dimer association and potentially alter monomer stability (Facchiano and Marabotti. 2010. PubMed ID: 20008339; Boutron et al. 2012. PubMed ID: 22944367). A different substitution of the same amino acid (p.Arg231Cys) has also been reported in association with galactosemia (e.g., Boutron et al. 2012. PubMed ID: 22944367; Coelho et al. 2014. PubMed ID: 25614870). This variant is interpreted as pathogenic. (less)
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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 |
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Clinical profile and molecular characterization of Galactosemia in Brazil: identification of seven novel mutations. | Garcia DF | BMC medical genetics | 2016 | PMID: 27176039 |
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 |
Galactosemia in the Turkish population with a high frequency of Q188R mutation and distribution of Duarte-1 and Duarte-2 variations. | Özgül RK | Journal of human genetics | 2013 | PMID: 23924834 |
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 |
Analysis of galactosemia-linked mutations of GALT enzyme using a computational biology approach. | Facchiano A | Protein engineering, design & selection : PEDS | 2010 | PMID: 20008339 |
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 basis for phenotypic heterogeneity in galactosaemia: prediction of clinical phenotype from genotype in Japanese patients. | Hirokawa H | European journal of human genetics : EJHG | 1999 | PMID: 10573007 |
Molecular characterization of galactosemia (type 1) mutations in Japanese. | Ashino J | Human mutation | 1995 | PMID: 7550229 |
Text-mined citations for rs111033754 ...
HelpRecord last updated Oct 13, 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.