ClinVar Genomic variation as it relates to human health
NM_001008216.2(GALE):c.1004G>A (p.Arg335His)
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_001008216.2(GALE):c.1004G>A (p.Arg335His)
Variation ID: 2503917 Accession: VCV002503917.3
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.11 1: 23795992 (GRCh38) [ NCBI UCSC ] 1: 24122482 (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 Jun 4, 2023 Feb 14, 2024 Aug 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001008216.2:c.1004G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001008217.1:p.Arg335His missense NM_000403.3:c.1004G>A NM_000403.4:c.1004G>A NP_000394.2:p.Arg335His missense NM_001127621.2:c.1004G>A NP_001121093.1:p.Arg335His missense NC_000001.11:g.23795992C>T NC_000001.10:g.24122482C>T NG_007068.1:g.9813G>A - Protein change
- R335H
- Other names
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- Canonical SPDI
- NC_000001.11:23795991:C:T
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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.
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- Links
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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GALE | - | - |
GRCh38 GRCh37 |
358 | 379 |
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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Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 29, 2023 | RCV003230908.2 | |
GALE-related disorder
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Likely pathogenic (1) |
criteria provided, single submitter
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Jan 3, 2023 | RCV003420622.5 |
Submissions - Germline
Classification
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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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Likely pathogenic
(Apr 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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UDPglucose-4-epimerase deficiency
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003928967.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
Variant summary: GALE c.1004G>A (p.Arg335His) 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: GALE c.1004G>A (p.Arg335His) 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 1.2e-05 in 250928 control chromosomes. c.1004G>A has been reported in the literature in at least two compound heterozygous newborns with severely reduced enzyme activity in red blood cells, but without obvious clinical symptoms, suggesting that they had the benign- or peripheral form of UDPglucose-4-Epimerase Deficiency (Park_2005), and in at least another individual with epimerase-deficiency galactosemia, however no phenotype details were provided (Henderson_2001). Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated a moderate decrease in UDP-galactose epimerization activity, ranging from ~40 to 70% of the wild-type (Timson_2005, Bang_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19250319, 16302980, 16301867, 11903335). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified for the peripheral form of the disease as likely pathogenic. (less)
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Likely pathogenic
(Jan 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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GALE-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004108072.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The GALE c.1004G>A variant is predicted to result in the amino acid substitution p.Arg335His. This variant has been reported in the compound heterozygous state in … (more)
The GALE c.1004G>A variant is predicted to result in the amino acid substitution p.Arg335His. This variant has been reported in the compound heterozygous state in two individuals with galactosaemia epimerase deficiency (Park et al 2005. PubMed ID: 16301867; 2005. PubMed ID: 16302980). Arg335 is located on α-helix 10 on the protein surface (McCorvie et al. 2013. PubMed ID: 23644136). Functional studies showed that this variant causes mild defects in enzyme activity (Timson et al. 2005. PubMed ID: 16302980; Bang YL et al 2009. PubMed ID: 19250319). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-24122482-C-T). This variant is interpreted as likely pathogenic. (less)
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Likely pathogenic
(Aug 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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UDPglucose-4-epimerase deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004291758.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects GALE function (PMID: 16302980, 19250319). 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 not expected to disrupt GALE protein function. ClinVar contains an entry for this variant (Variation ID: 2503917). This missense change has been observed in individual(s) with galactosemia (PMID: 16301867). This variant is present in population databases (rs368637540, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 335 of the GALE protein (p.Arg335His). (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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Functional analysis of mutations in UDP-galactose-4-epimerase (GALE) associated with galactosemia in Korean patients using mammalian GALE-null cells. | Bang YL | The FEBS journal | 2009 | PMID: 19250319 |
Functional analysis of disease-causing mutations in human UDP-galactose 4-epimerase. | Timson DJ | The FEBS journal | 2005 | PMID: 16302980 |
The molecular basis of UDP-galactose-4-epimerase (GALE) deficiency galactosemia in Korean patients. | Park HD | Genetics in medicine : official journal of the American College of Medical Genetics | 2005 | PMID: 16301867 |
A PCR-based method for detecting known mutations in the human UDP galactose-4'-epimerase gene associated with epimerase-deficiency galactosemia. | Henderson JM | Clinical genetics | 2001 | PMID: 11903335 |
Text-mined citations for this variant ...
HelpRecord last updated Jun 23, 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.