NM_000153.4(GALC):c.1004A>G (p.Tyr335Cys) AND Galactosylceramide beta-galactosidase deficiency

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 6, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000806470.10

Allele description [Variation Report for NM_000153.4(GALC):c.1004A>G (p.Tyr335Cys)]

NM_000153.4(GALC):c.1004A>G (p.Tyr335Cys)

Gene:

GALC:galactosylceramidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q31.3

Genomic location:

Preferred name:

NM_000153.4(GALC):c.1004A>G (p.Tyr335Cys)

HGVS:

NC_000014.9:g.87965534T>C
NG_011853.3:g.33030A>G
NM_000153.4:c.1004A>GMANE SELECT
NM_001201401.2:c.935A>G
NM_001201402.2:c.926A>G
NP_000144.2:p.Tyr335Cys
NP_001188330.1:p.Tyr312Cys
NP_001188331.1:p.Tyr309Cys
NC_000014.8:g.88431878T>C
NG_011853.2:g.33030A>G
NM_000153.3:c.1004A>G

Protein change:

Y309C

Links:

dbSNP: rs757407613

NCBI 1000 Genomes Browser:

rs757407613

Molecular consequence:

NM_000153.4:c.1004A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001201401.2:c.935A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001201402.2:c.926A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Galactosylceramide beta-galactosidase deficiency
Synonyms:: Krabbe leukodystrophy; Globoid cell leukoencephalopathy; Galactocerebrosidase deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009499; MedGen: C0023521; Orphanet: 487; OMIM: 245200

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000946473	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 6, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 27126738, 27638593, 10234611, 22115770, 28492532
SCV002093639	Natera, Inc.	no assertion criteria provided	Pathogenic (Aug 27, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000946473

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 6, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002093639

Natera, Inc.

no assertion criteria provided

Pathogenic
(Aug 27, 2020)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular Mechanisms of Disease Pathogenesis Differ in Krabbe Disease Variants.

Spratley SJ, Hill CH, Viuff AH, Edgar JR, Skjødt K, Deane JE.

Traffic. 2016 Aug;17(8):908-22. doi: 10.1111/tra.12404. Epub 2016 May 30.

PubMed [citation]

PMID:: 27126738
PMCID:: PMC4949656

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, Luzi P, Nichols M, Orsini JJ, Caggana M, Wenger DA.

J Neurosci Res. 2016 Nov;94(11):1076-83. doi: 10.1002/jnr.23905.

PubMed [citation]

PMID:: 27638593

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000946473.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GALC function (PMID: 10234611, 27126738, 27638593). 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. ClinVar contains an entry for this variant (Variation ID: 651170). This missense change has been observed in individual(s) with infantile Krabbe disease (PMID: 10234611, 22115770). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs757407613, gnomAD 0.003%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 335 of the GALC protein (p.Tyr335Cys).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002093639.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

ClinVar

Relating variation to medicine