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

Clinical significance:Pathogenic (Last evaluated: Nov 16, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000806470.3

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_011853.2:g.33030A>G
  • NM_000153.4:c.1004A>GMANE SELECT
  • NM_001201401.1:c.935A>G
  • NM_001201402.1:c.926A>G
  • NP_000144.2:p.Tyr335Cys
  • NP_001188330.1:p.Tyr312Cys
  • NP_001188331.1:p.Tyr309Cys
  • NC_000014.8:g.88431878T>C
  • 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_001201401.1:c.935A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001201402.1: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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000946473Invitaecriteria provided, single submitter
Pathogenic
(Nov 16, 2019)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Krabbe disease: clinical, biochemical and molecular information on six new patients and successful retrospective diagnosis using stored newborn screening cards.

Puckett RL, Orsini JJ, Pastores GM, Wang RY, Chang R, Saavedra-Matiz CA, Torres PA, Zeng B, Caggana M, Lorey F, Abdenur JE.

Mol Genet Metab. 2012 Jan;105(1):126-31. doi: 10.1016/j.ymgme.2011.10.010. Epub 2011 Oct 25.

PubMed [citation]
PMID:
22115770

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
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000946473.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces tyrosine with cysteine at codon 335 of the GALC protein (p.Tyr335Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs757407613, ExAC 0.003%). This variant has been observed in individual(s) with infantile Krabbe disease (PMID: 10234611, 22115770). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported to affect GALC protein function (PMID: 27126738, 10234611, 27638593). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 10, 2021

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