ClinVar Genomic variation as it relates to human health
NM_000153.4(GALC):c.908C>T (p.Ser303Phe)
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_000153.4(GALC):c.908C>T (p.Ser303Phe)
Variation ID: 280957 Accession: VCV000280957.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q31.3 14: 87968335 (GRCh38) [ NCBI UCSC ] 14: 88434679 (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 Dec 6, 2016 May 12, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000153.4:c.908C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000144.2:p.Ser303Phe missense NM_001201401.2:c.839C>T NP_001188330.1:p.Ser280Phe missense NM_001201402.2:c.830C>T NP_001188331.1:p.Ser277Phe missense NC_000014.9:g.87968335G>A NC_000014.8:g.88434679G>A NG_011853.3:g.30229C>T P54803:p.Ser303Phe - Protein change
- S303F, S277F, S280F
- Other names
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- Canonical SPDI
- NC_000014.9:87968334: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) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00004
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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GALC | - | - |
GRCh38 GRCh37 |
1313 | 1426 |
Conditions - Germline
Condition
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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
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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 (9) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2024 | RCV000285229.19 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Aug 7, 2023 | RCV000522818.27 |
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
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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
(Mar 29, 2017)
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criteria provided, single submitter
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000800751.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Pathogenic
(Sep 29, 2015)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000330944.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 5
Sex: mixed
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Pathogenic
(May 03, 2018)
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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
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Illumina Laboratory Services, Illumina
Accession: SCV000389254.3
First in ClinVar: Dec 06, 2016 Last updated: May 27, 2019 |
Comment:
The GALC c.908C>T (p.Ser303Phe) missense variant, also referred to as p.Ser287Phe, has been reported in at least four studies in which it is found in … (more)
The GALC c.908C>T (p.Ser303Phe) missense variant, also referred to as p.Ser287Phe, has been reported in at least four studies in which it is found in a total of five unrelated individuals, all affected with an infantile form of galactosylceramide beta-galactosidase deficiency disease (Krabbe disease), including in one in a homozygous state and four in a compound heterozygous state (Wenger et al. 1997; Selleri et al. 2000; Tappino et al. 2010; Zhao et al. 2017). GALC activity in patient leukocytes or fibroblasts ranged from 3 - 15% compared to control levels. All of the compound heterozygotes carried missense variants on the second allele, with one found in trans with a complex allele of two missense variants. Control data are unavailable for this variant, which is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. The serine residue is partially conserved. Expression of the variant in COS-1 cells revealed no GALC activity in vitro (Jardim et al. 1999). Based on the evidence, the p.Ser303Phe variant is classified as pathogenic for Krabbe disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Aug 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000617679.2
First in ClinVar: Dec 19, 2017 Last updated: Aug 18, 2023 |
Comment:
Expression studies on COS-1 cells showed a dramatic reduction of GALC activity of the mutated expressed protein (Jardim et al., 1999); In silico analysis supports … (more)
Expression studies on COS-1 cells showed a dramatic reduction of GALC activity of the mutated expressed protein (Jardim et al., 1999); 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 (gnomAD); This variant is associated with the following publications: (PMID: 9338580, 20886637, 28598007, 33176815, 30089515, 11151421, 10448809) (less)
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Pathogenic
(Mar 04, 2020)
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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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Revvity Omics, Revvity
Accession: SCV002021213.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 18, 2023)
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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
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Invitae
Accession: SCV001224311.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 303 of the GALC protein (p.Ser303Phe). … (more)
This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 303 of the GALC protein (p.Ser303Phe). This variant is present in population databases (rs756352952, gnomAD 0.004%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 9338580, 11151421, 20886637, 30089515). This variant is also known as Ser287Phe. ClinVar contains an entry for this variant (Variation ID: 280957). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GALC function (PMID: 10448809). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249967.21
First in ClinVar: May 09, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Mar 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002318482.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000280957, PMID:9338580). Functional studies … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000280957, PMID:9338580). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10448809). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.957>=0.6, 3CNET: 0.946>=0.75). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000284). The variant is in trans with NM_000153.4:c.136G>T variant (3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Abnormal circulating glutamine concentration (present) , Increased CSF protein concentration (present) , Cerebral dysmyelination (present) , Leukodystrophy (present) , Dysmyelinating leukodystrophy (present) , Hyperreflexia (present) … (more)
Abnormal circulating glutamine concentration (present) , Increased CSF protein concentration (present) , Cerebral dysmyelination (present) , Leukodystrophy (present) , Dysmyelinating leukodystrophy (present) , Hyperreflexia (present) , Increased susceptibility to fractures (present) , Generalized hypotonia (present) , Maculopapular exanthema (present) , Developmental regression (present) (less)
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Likely pathogenic
(May 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002801173.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 22, 2023)
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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
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922542.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: GALC c.908C>T (p.Ser303Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: GALC c.908C>T (p.Ser303Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Two computational tools predict a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 245686 control chromosomes (gnomAD). c.908C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Krabbe Disease, primarily with infantile onset (e.g. Wenger_1997, Selleri_2000, Tappino_2010, Zhao_2018, Krieg_2020). These data indicate that the variant is very likely to be associated with disease. Ten submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=8)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047462.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense variant c.908C>T (p.Ser303Phe) in GALC gene has been reported in heterozygous state in several individuals affected with Krabbe disease (Bascou N et al.). … (more)
The missense variant c.908C>T (p.Ser303Phe) in GALC gene has been reported in heterozygous state in several individuals affected with Krabbe disease (Bascou N et al.). The S303F was also reported in a patient with infantile-onset Krabbe disease who was homozygous for S303F (Wenger et al.). Experimental studies have shown that predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies (Jardim et al.). This variant has allele frequency 0.002% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The S303F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The amino acid change p.Ser303Phe in GALC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Tremor (present) , Hyperintensity of cerebral white matter on MRI (present) , Abnormal cerebral morphology (present) , Leukodystrophy (present) , Neurodegeneration (present)
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Pathogenic
(Mar 29, 2024)
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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
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807503.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Jun 03, 2021)
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no assertion criteria provided
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002093643.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Natural history of Krabbe disease - a nationwide study in Germany using clinical and MRI data. | Krieg SI | Orphanet journal of rare diseases | 2020 | PMID: 32912261 |
A prospective natural history study of Krabbe disease in a patient cohort with onset between 6 months and 3 years of life. | Bascou N | Orphanet journal of rare diseases | 2018 | PMID: 30089515 |
Large-scale study of clinical and biochemical characteristics of Chinese patients diagnosed with Krabbe disease. | Zhao S | Clinical genetics | 2018 | PMID: 28598007 |
Insights into Krabbe disease from structures of galactocerebrosidase. | Deane JE | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 21876145 |
Identification and characterization of 15 novel GALC gene mutations causing Krabbe disease. | Tappino B | Human mutation | 2010 | PMID: 20886637 |
Deletion of exons 11-17 and novel mutations of the galactocerebrosidase gene in adult- and early-onset patients with Krabbe disease. | Selleri S | Journal of neurology | 2000 | PMID: 11151421 |
Protracted course of Krabbe disease in an adult patient bearing a novel mutation. | Jardim LB | Archives of neurology | 1999 | PMID: 10448809 |
Molecular genetics of Krabbe disease (globoid cell leukodystrophy): diagnostic and clinical implications. | Wenger DA | Human mutation | 1997 | PMID: 9338580 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GALC | - | - | - | - |
Text-mined citations for rs756352952 ...
HelpRecord last updated May 12, 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.