This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 544 of the GALC protein (p.Asp544Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with the infantile Krabbe disease (PMID: 8786069, 12699861). This variant is also known as c.1582G>A, p.D528N. ClinVar contains an entry for this variant (Variation ID: 30614). 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. Experimental studies have shown that this missense change affects GALC function (PMID: 26865610). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000153.4(GALC):c.1630G>A (p.Asp544Asn)
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.
(11)
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/Likely pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000153.4(GALC):c.1630G>A (p.Asp544Asn)
Variation ID: 30614 Accession: VCV000030614.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 14q31.3 14: 87945593 (GRCh38) [ NCBI UCSC ] 14: 88411937 (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 Jul 29, 2024 Jul 20, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000153.4:c.1630G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000144.2:p.Asp544Asn missense NM_001201401.2:c.1561G>A NP_001188330.1:p.Asp521Asn missense NM_001201402.2:c.1552G>A NP_001188331.1:p.Asp518Asn missense NC_000014.9:g.87945593C>T NC_000014.8:g.88411937C>T NG_011853.3:g.52971G>A P54803:p.Asp544Asn - Protein change
- D544N, D518N, D521N
- Other names
- -
- Canonical SPDI
- NC_000014.9:87945592:C:T
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 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 |
1327 | 1440 | |
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/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Jul 20, 2024 | RCV000023588.14 | |
| Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 14, 2023 | RCV001270016.8 |
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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Pathogenic
(Apr 26, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000790762.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
|
|
|
Pathogenic
(May 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002245357.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 544 of the GALC protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 544 of the GALC protein (p.Asp544Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with the infantile Krabbe disease (PMID: 8786069, 12699861). This variant is also known as c.1582G>A, p.D528N. ClinVar contains an entry for this variant (Variation ID: 30614). 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. Experimental studies have shown that this missense change affects GALC function (PMID: 26865610). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Galactosylceramide beta-galactosidase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557059.2
First in ClinVar: Aug 04, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Krabbe disease (MIM#245200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has previous evidence of pathogenicity in unrelated individuals. This variant is found at high frequency in affected individuals from a specific region, likely representing a founder effect (PMID: 8786069, 12699861). (SP) 0901 - This variant has strong evidence for segregation with disease. Rafi et al identified this variant in six homozygous affected individuals and seven obligate heterozygotes from an inbred population (PMID: 8786069). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional assays in cell lines have shown this variant to result in reduced enzyme activity, protein instability, impaired trafficking, and hyperglycosylation of the GALC protein (PMID: 20410102, 26865610). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(Jul 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Galactosylceramide beta-galactosidase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV005073724.1
First in ClinVar: Jul 29, 2024 Last updated: Jul 29, 2024 |
Comment:
This patient was heterozygous of two known very rare variants, c.1630G>A and c.658C>T, in the GALC gene. The c.658C>T variant is predicted to result in … (more)
This patient was heterozygous of two known very rare variants, c.1630G>A and c.658C>T, in the GALC gene. The c.658C>T variant is predicted to result in premature protein termination (p.Arg220Ter). These variants have been reported for their pathogenicity in ClinVar. Both variants were segregated within the family using Sanger sequencing. (less)
Age: 0-9 years
Sex: female
Geographic origin: Iran
|
|
|
Likely pathogenic
(Aug 06, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450435.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 3
|
|
|
Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002516432.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
|
Likely pathogenic
(Jul 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Galactosylceramide beta-galactosidase deficiency
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003806919.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderated, PM3 supporting, PP4
Number of individuals with the variant: 1
Clinical Features:
Primary Caesarian section (present) , Severe global developmental delay (present) , Abnormal delivery (present) , Generalized-onset seizure (present) , Spastic tetraplegia (present) , Delayed gross … (more)
Primary Caesarian section (present) , Severe global developmental delay (present) , Abnormal delivery (present) , Generalized-onset seizure (present) , Spastic tetraplegia (present) , Delayed gross motor development (present) , Delayed fine motor development (present) , Caesarian section (present) , Motor delay (present) , Intellectual disability, moderate (present) , Absent speech (present) , Delayed speech and language development (present) , Tetraplegia (present) , Spasticity (present) , Global developmental delay (present) , Profound global developmental delay (present) , Bilateral tonic-clonic seizure (present) , Seizure (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
|
|
Likely pathogenic
(Jun 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002025242.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001959372.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(Dec 01, 2010)
|
no assertion criteria provided
Method: literature only
|
KRABBE DISEASE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000044879.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 25, 2021 |
Comment on evidence:
In affected individuals from an inbred Arab Israeli population with infantile Krabbe disease (KRB; 245200), Rafi et al. (1996) identified a homozygous 1630G-A transition in … (more)
In affected individuals from an inbred Arab Israeli population with infantile Krabbe disease (KRB; 245200), Rafi et al. (1996) identified a homozygous 1630G-A transition in exon 14 of the GALC gene, resulting in an asp544-to-asn (D544N) substitution in the 30-kD subunit. The findings were consistent with a founder effect. In vitro functional expression studies showed that the mutant protein had no enzymatic activity. This mutation, originally reported as ASP528ASN, has been renumbered based on the first ATG initiation codon as nucleotide +1 (Tappino et al., 2010). (less)
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001974848.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
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| click to load more click to collapse | |||||
Comment:
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Krabbe disease (MIM#245200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has previous evidence of pathogenicity in unrelated individuals. This variant is found at high frequency in affected individuals from a specific region, likely representing a founder effect (PMID: 8786069, 12699861). (SP) 0901 - This variant has strong evidence for segregation with disease. Rafi et al identified this variant in six homozygous affected individuals and seven obligate heterozygotes from an inbred population (PMID: 8786069). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional assays in cell lines have shown this variant to result in reduced enzyme activity, protein instability, impaired trafficking, and hyperglycosylation of the GALC protein (PMID: 20410102, 26865610). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
This patient was heterozygous of two known very rare variants, c.1630G>A and c.658C>T, in the GALC gene. The c.658C>T variant is predicted to result in premature protein termination (p.Arg220Ter). These variants have been reported for their pathogenicity in ClinVar. Both variants were segregated within the family using Sanger sequencing.
Comment:
ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderated, PM3 supporting, PP4
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:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 544 of the GALC protein (p.Asp544Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with the infantile Krabbe disease (PMID: 8786069, 12699861). This variant is also known as c.1582G>A, p.D528N. ClinVar contains an entry for this variant (Variation ID: 30614). 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. Experimental studies have shown that this missense change affects GALC function (PMID: 26865610). For these reasons, this variant has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Krabbe disease (MIM#245200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has previous evidence of pathogenicity in unrelated individuals. This variant is found at high frequency in affected individuals from a specific region, likely representing a founder effect (PMID: 8786069, 12699861). (SP) 0901 - This variant has strong evidence for segregation with disease. Rafi et al identified this variant in six homozygous affected individuals and seven obligate heterozygotes from an inbred population (PMID: 8786069). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional assays in cell lines have shown this variant to result in reduced enzyme activity, protein instability, impaired trafficking, and hyperglycosylation of the GALC protein (PMID: 20410102, 26865610). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
This patient was heterozygous of two known very rare variants, c.1630G>A and c.658C>T, in the GALC gene. The c.658C>T variant is predicted to result in premature protein termination (p.Arg220Ter). These variants have been reported for their pathogenicity in ClinVar. Both variants were segregated within the family using Sanger sequencing.
Comment:
ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderated, PM3 supporting, PP4
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Altered Trafficking and Processing of GALC Mutants Correlates with Globoid Cell Leukodystrophy Severity. | Shin D | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2016 | PMID: 26865610 |
| 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 |
| Molecular characterization of mutations that cause globoid cell leukodystrophy and pharmacological rescue using small molecule chemical chaperones. | Lee WC | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2010 | PMID: 20410102 |
| Early peripheral nervous system manifestations of infantile Krabbe disease. | Korn-Lubetzki I | Pediatric neurology | 2003 | PMID: 12699861 |
| Two different mutations are responsible for Krabbe disease in the Druze and Moslem Arab populations in Israel. | Rafi MA | Human genetics | 1996 | PMID: 8786069 |
Text-mined citations for rs387906952 ...
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 Sep 29, 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.