Variant summary: The GALC c.169G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Ser. 5/5 in-silico tools predict damaging outcome for this variant. This variant has been reported in at least 5 patients with late onset Krabbe disease in both homozygous and compound heterozygous state. This variant was not found in 16310 control chromosomes. In addition, one clinical laboratory classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000153.4(GALC):c.169G>A (p.Gly57Ser)
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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000153.4(GALC):c.169G>A (p.Gly57Ser)
Variation ID: 193054 Accession: VCV000193054.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q31.3 14: 87992996 (GRCh38) [ NCBI UCSC ] 14: 88459340 (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 28, 2015 Feb 20, 2024 Dec 5, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000153.4:c.169G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000144.2:p.Gly57Ser missense NM_001201401.2:c.169G>A NP_001188330.1:p.Gly57Ser missense NM_001201402.2:c.117+387G>A intron variant NC_000014.9:g.87992996C>T NC_000014.8:g.88459340C>T NG_011853.3:g.5568G>A - Protein change
- G57S
- Other names
- -
- Canonical SPDI
- NC_000014.9:87992995: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
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 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. |
|||
| GALC | - | - |
GRCh38 GRCh37 |
1337 | 1451 | |
| LOC130056217 | - | - | - | GRCh38 | - | 87 |
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 (3) |
criteria provided, multiple submitters, no conflicts
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Dec 5, 2023 | RCV000173074.7 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 31, 2023 | RCV000498062.10 |
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
(Mar 10, 2016)
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criteria provided, single submitter
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695672.1
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Comment:
Variant summary: The GALC c.169G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Ser. 5/5 in-silico tools predict damaging outcome … (more)
Variant summary: The GALC c.169G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Ser. 5/5 in-silico tools predict damaging outcome for this variant. This variant has been reported in at least 5 patients with late onset Krabbe disease in both homozygous and compound heterozygous state. This variant was not found in 16310 control chromosomes. In addition, one clinical laboratory classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. (less)
|
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Pathogenic
(Oct 16, 2014)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000224158.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: mixed
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Pathogenic
(Oct 29, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000589329.5
First in ClinVar: Aug 20, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: cells expressing the G57S variant have undetectable GALC activity in comparison to wild type (Lissens et al., 2007); … (more)
Published functional studies demonstrate a damaging effect: cells expressing the G57S variant have undetectable GALC activity in comparison to wild type (Lissens et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Also known as Gly41Ser (G41S); This variant is associated with the following publications: (PMID: 27638593, 27126738, 17579360, 21070211) (less)
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Pathogenic
(Mar 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004236684.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003784050.3
First in ClinVar: Feb 13, 2023 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 57 of the GALC protein (p.Gly57Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 57 of the GALC protein (p.Gly57Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Krabbe disease (PMID: 17579360, 21070211). This variant is also known as c.121G>A; p.Gly41Ser. ClinVar contains an entry for this variant (Variation ID: 193054). 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 GALC protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALC function (PMID: 27126738). This variant disrupts the p.Gly57 amino acid residue in GALC. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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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not provided
(-)
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no classification provided
Method: literature only
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Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV004035013.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
|
Comment:
Comment:
Published functional studies demonstrate a damaging effect: cells expressing the G57S variant have undetectable GALC activity in comparison to wild type (Lissens et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Also known as Gly41Ser (G41S); This variant is associated with the following publications: (PMID: 27638593, 27126738, 17579360, 21070211)
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 57 of the GALC protein (p.Gly57Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Krabbe disease (PMID: 17579360, 21070211). This variant is also known as c.121G>A; p.Gly41Ser. ClinVar contains an entry for this variant (Variation ID: 193054). 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 GALC protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALC function (PMID: 27126738). This variant disrupts the p.Gly57 amino acid residue in GALC. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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.
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 GALC c.169G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Ser. 5/5 in-silico tools predict damaging outcome for this variant. This variant has been reported in at least 5 patients with late onset Krabbe disease in both homozygous and compound heterozygous state. This variant was not found in 16310 control chromosomes. In addition, one clinical laboratory classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Comment:
Published functional studies demonstrate a damaging effect: cells expressing the G57S variant have undetectable GALC activity in comparison to wild type (Lissens et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Also known as Gly41Ser (G41S); This variant is associated with the following publications: (PMID: 27638593, 27126738, 17579360, 21070211)
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 57 of the GALC protein (p.Gly57Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Krabbe disease (PMID: 17579360, 21070211). This variant is also known as c.121G>A; p.Gly41Ser. ClinVar contains an entry for this variant (Variation ID: 193054). 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 GALC protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALC function (PMID: 27126738). This variant disrupts the p.Gly57 amino acid residue in GALC. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Krabbe Disease. | Adam MP | - | 2018 | PMID: 20301416 |
| Molecular Mechanisms of Disease Pathogenesis Differ in Krabbe Disease Variants. | Spratley SJ | Traffic (Copenhagen, Denmark) | 2016 | PMID: 27126738 |
| History, genetic, and recent advances on Krabbe disease. | Graziano AC | Gene | 2015 | PMID: 25260228 |
| Krabbe leukodystrophy in a selected population with high rate of late onset forms: longer survival linked to c.121G>A (p.Gly41Ser) mutation. | Fiumara A | Clinical genetics | 2011 | PMID: 21070211 |
| A single mutation in the GALC gene is responsible for the majority of late onset Krabbe disease patients in the Catania (Sicily, Italy) region. | Lissens W | Human mutation | 2007 | PMID: 17579360 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GALC | - | - | - | - |
Text-mined citations for rs11623 ...
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 Jan 13, 2025
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.