ClinVar Genomic variation as it relates to human health
NM_000153.4(GALC):c.1901T>C (p.Leu634Ser)
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.1901T>C (p.Leu634Ser)
Variation ID: 225368 Accession: VCV000225368.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q31.3 14: 87939915 (GRCh38) [ NCBI UCSC ] 14: 88406259 (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 Feb 14, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000153.4:c.1901T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000144.2:p.Leu634Ser missense NM_001201401.2:c.1832T>C NP_001188330.1:p.Leu611Ser missense NM_001201402.2:c.1823T>C NP_001188331.1:p.Leu608Ser missense NC_000014.9:g.87939915A>G NC_000014.8:g.88406259A>G NG_011853.3:g.58649T>C P54803:p.Leu634Ser - Protein change
- L634S, L611S, L608S
- Other names
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- Canonical SPDI
- NC_000014.9:87939914:A:G
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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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0.00160 (G)
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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) 0.00018
Trans-Omics for Precision Medicine (TOPMed) 0.00049
The Genome Aggregation Database (gnomAD), exomes 0.00065
Exome Aggregation Consortium (ExAC) 0.00069
1000 Genomes Project 30x 0.00141
1000 Genomes Project 0.00160
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
Help
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
Help
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 (11) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000345880.28 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 28, 2023 | RCV001785518.7 |
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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Likely pathogenic
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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Galactosylceramide beta-galactosidase deficiency
Affected status: unknown
Allele origin:
germline
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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267329.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 1
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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Pathogenic
(-)
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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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Baylor Genetics
Accession: SCV001163745.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
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Pathogenic
(May 12, 2022)
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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: SCV002021226.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 31, 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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Invitae
Accession: SCV000835189.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 634 of the GALC protein (p.Leu634Ser). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 634 of the GALC protein (p.Leu634Ser). This variant is present in population databases (rs138577661, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Krabbe disease (PMID: 9272171, 16607461, 24252386, 26865610, 27679535, 27780934). This variant is also known as Leu618Ser. ClinVar contains an entry for this variant (Variation ID: 225368). 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: 9272171, 24252386, 27126738, 27638593, 27780934). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 12, 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
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695674.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
Variant summary: The GALC c.1901T>C (p.Leu634Ser) variant, alternatively also known was L618S, involves the alteration of a highly conserved nucleotide and is located in Glyco_hydro_59 … (more)
Variant summary: The GALC c.1901T>C (p.Leu634Ser) variant, alternatively also known was L618S, involves the alteration of a highly conserved nucleotide and is located in Glyco_hydro_59 domain of the protein. 4/4 in silico tools predict a damaging outcome for this variant. This variant was found in 83/120532 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0090487 (78/8620). No homozygotes have been reported in general population. In literature, this variant is widely reported as a mild pathogenic variant that causes later-onset Krabbe disease (KD) and is found in several KD patients in homozygous, compound heterozygous and heterozygous states. The variants frequency is high in Japanese patients; a study has reported its allele frequency at 10.7% (11/102 alleles) in a Japanese patient cohort (Hossain_2013). Available functional assays (enzymatic as well as processing assay) further support the variant as a pathogenic variant with ~10% GALC activity in transfected cells. There is some conflicting functional data on the proper localization of the mutant with Shin_2016 and Lim_2016 reporting proper localization while Spratley_2016 reports improper localization. Taken together, this variant is classified as Pathogenic. (less)
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Likely pathogenic
(Apr 05, 2019)
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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: SCV000389235.3
First in ClinVar: Dec 06, 2016 Last updated: May 27, 2019 |
Comment:
Across a selection of the available literature, the GALC c.1901T>C (p.Leu634Ser) missense variant, also referred to as p.Leu618Ser, has been identified in 12 individuals affected … (more)
Across a selection of the available literature, the GALC c.1901T>C (p.Leu634Ser) missense variant, also referred to as p.Leu618Ser, has been identified in 12 individuals affected with Krabbe disease, including in a homozygous state in one individual, in a compound heterozygous state in eight individuals, and in a heterozygous state in three individuals. All affected individuals were of Asian descent and have a variable age of onset of Krabbe disease ranging from late-infantile to adult (Furuya et al. 1997; Satoh et al. 1997; Xu et al. 2006; Hossain et al. 2014; Lim et al. 2016; Yoshimura et al. 2016). The p.Leu634Ser variant was also reported in seven asymptomatic newborns including in five in a homozygous state and in two in a compound heterozygous state (Orsini et al. 2016). In the five asymptomatic homozygous newborns, additional GALC variants were detected in cis with the p.Leu634Ser variant. GALC activity was used to assess risk of developing Krabbe disease, with one infant classified as high-risk, one as low-risk, and three as moderate-risk (Orsini et al. 2016). The p.Leu634Ser variant was absent from 65 controls (Furuya et al. 1997), but is reported at a frequency of 0.01923 in the Japanese population of the 1000 Genomes Project. Expression of the p.Leu634Ser variant in COS-1 cells resulted in an approximately 90% reduction in enzyme activity when compared to wild-type (Furuya et al. 1997; Satoh et al. 1997; Shin et al. 2016). Another study demonstrated lack of secretion of the p.Leu634Ser variant protein in transfected HEK293T cells, and also suggested that presence of the variant reduced trafficking of the GALC protein to lysosomes, although a second study showed localization in lysosomes (Spratley et al. 2016; Shin et al. 2016). Despite the high allele frequency, based on the collective clinical evidence, the p.Leu634Ser variant is classified as likely 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
(Dec 31, 2019)
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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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Myriad Genetics, Inc.
Accession: SCV001193893.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000153.3(GALC):c.1901T>C(L634S) is classified as pathogenic in the context of Krabbe disease and may be associated with a late-onset form of disease. Sources cited for classification … (more)
NM_000153.3(GALC):c.1901T>C(L634S) is classified as pathogenic in the context of Krabbe disease and may be associated with a late-onset form of disease. Sources cited for classification include the following: PMID 29951496, 29966168, 30089515, 27638604, 26865610, 27126738, 24252386, 9272171, 26795590, 27780934 and 27679535. Classification of NM_000153.3(GALC):c.1901T>C(L634S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Likely pathogenic
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Galactosylceramide beta-galactosidase deficiency
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001810430.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Likely pathogenic
(Jan 11, 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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MGZ Medical Genetics Center
Accession: SCV002580670.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4_MOD, PM2_SUP, PP2, PP3
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Number of individuals with the variant: 2
Sex: female
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Pathogenic
(Apr 28, 2023)
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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: SCV004226675.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 16, 2020)
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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: SCV001464120.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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
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GeneReviews
Accession: SCV004035010.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
Comment:
One copy of this allele together with another severe allele in the homozygous state is associated with late-onset disease.
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Benign
(May 10, 2019)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Galactosylceramide beta-galactosidase deficiency
Affected status: yes
Allele origin:
paternal
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Center for Molecular Medicine, Children’s Hospital of Fudan University
Accession: SCV001190543.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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A novel GALC gene mutation associated with adult-onset Krabbe disease: a case report. | He Z | Neurocase | 2022 | PMID: 35654103 |
Pathogenic Variants in GALC Gene Correlate With Late Onset Krabbe Disease and Vision Loss: Case Series and Review of Literature. | Bascou NA | Frontiers in neurology | 2020 | PMID: 33178108 |
Adult-onset Krabbe disease due to a homozygous GALC mutation without abnormal signals on an MRI in a consanguineous family: A case report. | Xia Z | Molecular genetics & genomic medicine | 2020 | PMID: 32677356 |
A new compound heterozygous mutation in adult-onset Krabbe disease. | Meng X | The International journal of neuroscience | 2020 | PMID: 32064984 |
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 |
Early prenatal diagnosis of lysosomal storage disorders by enzymatic and molecular analysis. | Li D | Prenatal diagnosis | 2018 | PMID: 29966168 |
Adult-onset Krabbe disease in two generations of a Chinese family. | Zhang T | Annals of translational medicine | 2018 | PMID: 29951496 |
Krabbe Disease. | Adam MP | - | 2018 | PMID: 20301416 |
Patient fibroblasts-derived induced neurons demonstrate autonomous neuronal defects in adult-onset Krabbe disease. | Lim SM | Oncotarget | 2016 | PMID: 27780934 |
Predominant Corticospinal Tract Involvement in a Late Infant with Krabbe Disease. | Yoshimura A | Japanese clinical medicine | 2016 | PMID: 27679535 |
New therapeutic approaches for Krabbe disease: The potential of pharmacological chaperones. | Spratley SJ | Journal of neuroscience research | 2016 | PMID: 27638604 |
Expression of individual mutations and haplotypes in the galactocerebrosidase gene identified by the newborn screening program in New York State and in confirmed cases of Krabbe's disease. | Saavedra-Matiz CA | Journal of neuroscience research | 2016 | PMID: 27638593 |
Molecular Mechanisms of Disease Pathogenesis Differ in Krabbe Disease Variants. | Spratley SJ | Traffic (Copenhagen, Denmark) | 2016 | PMID: 27126738 |
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 |
Newborn screening for Krabbe disease in New York State: the first eight years' experience. | Orsini JJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26795590 |
Late-onset Krabbe disease is predominant in Japan and its mutant precursor protein undergoes more effective processing than the infantile-onset form. | Hossain MA | Gene | 2014 | PMID: 24252386 |
Six novel mutations detected in the GALC gene in 17 Japanese patients with Krabbe disease, and new genotype-phenotype correlation. | Xu C | Journal of human genetics | 2006 | PMID: 16607461 |
Adult-onset Krabbe disease with homozygous T1853C mutation in the galactocerebrosidase gene. Unusual MRI findings of corticospinal tract demyelination. | Satoh JI | Neurology | 1997 | PMID: 9371928 |
Adult onset globoid cell leukodystrophy (Krabbe disease): analysis of galactosylceramidase cDNA from four Japanese patients. | Furuya H | Human genetics | 1997 | PMID: 9272171 |
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Text-mined citations for rs138577661 ...
HelpRecord last updated May 08, 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.