NM_000153.4(GALC):c.136G>T (p.Asp46Tyr) AND Galactosylceramide beta-galactosidase deficiency

Clinical significance:Pathogenic (Last evaluated: Apr 6, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000781395.4

Allele description [Variation Report for NM_000153.4(GALC):c.136G>T (p.Asp46Tyr)]

NM_000153.4(GALC):c.136G>T (p.Asp46Tyr)

Gene:
GALC:galactosylceramidase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q31.3
Genomic location:
Preferred name:
NM_000153.4(GALC):c.136G>T (p.Asp46Tyr)
HGVS:
  • NC_000014.9:g.87993029C>A
  • NG_011853.2:g.5535G>T
  • NM_000153.4:c.136G>TMANE SELECT
  • NM_001201401.1:c.136G>T
  • NM_001201402.1:c.117+354G>T
  • NP_000144.2:p.Asp46Tyr
  • NP_001188330.1:p.Asp46Tyr
  • NC_000014.8:g.88459373C>A
  • NM_000153.3:c.136G>T
Protein change:
D46Y
Links:
dbSNP: rs751975987
NCBI 1000 Genomes Browser:
rs751975987
Molecular consequence:
  • NM_001201402.1:c.117+354G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000153.4:c.136G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001201401.1:c.136G>T - 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
SCV000919391Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Dec 4, 2017)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000946629Invitaecriteria provided, single submitter
Pathogenic
(Apr 6, 2020)
germlineclinical testing

PubMed (4)
[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

Increased plasma oligomeric alpha-synuclein in patients with lysosomal storage diseases.

Pchelina SN, Nuzhnyi EP, Emelyanov AK, Boukina TM, Usenko TS, Nikolaev MA, Salogub GN, Yakimovskii AF, Zakharova EY.

Neurosci Lett. 2014 Nov 7;583:188-93. doi: 10.1016/j.neulet.2014.09.041. Epub 2014 Sep 26.

PubMed [citation]
PMID:
25265039

GALC mutations in Chinese patients with late-onset Krabbe disease: a case report.

Zhuang S, Kong L, Li C, Chen L, Zhang T.

BMC Neurol. 2019 Jun 11;19(1):122. doi: 10.1186/s12883-019-1345-z.

PubMed [citation]
PMID:
31185936
PMCID:
PMC6560759
See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919391.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: The GALC c.136G>T (p.Asp46Tyr) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 9/149232 control chromosomes at a frequency of 0.0000603, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALC variant (0.0022361). The variant was reported in several patients in compound heterozygosity with at least two likely pathogenic/pathogenic mutations and biochemical findings suggestive of Krabbe disease (Pchelina_2014; Zhao_2017). Per latest published reports, c.136G>T is associated with a mild clinical course of disease (Zhao_2017). Taken together, this variant is classified as Pathogenic.

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

From Invitae, SCV000946629.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces aspartic acid with tyrosine at codon 46 of the GALC protein (p.Asp46Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs751975987, ExAC 0.2%). This variant has been observed in individual(s) with Krabbe disease (PMID: 31185936, 24078576, 28598007, external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 633229). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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: Jun 14, 2021

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