NM_000153.4(GALC):c.1814dup (p.Tyr605Ter) AND Galactosylceramide beta-galactosidase deficiency

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Sep 1, 2019)

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:
RCV000781391.3

Allele description [Variation Report for NM_000153.4(GALC):c.1814dup (p.Tyr605Ter)]

NM_000153.4(GALC):c.1814dup (p.Tyr605Ter)

Gene:
GALC:galactosylceramidase [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
14q31.3
Genomic location:
Preferred name:
NM_000153.4(GALC):c.1814dup (p.Tyr605Ter)
HGVS:
  • NC_000014.9:g.87941415dup
  • NG_011853.2:g.57149dup
  • NG_011853.3:g.57149dup
  • NM_000153.4:c.1814dupMANE SELECT
  • NM_001201401.2:c.1745dup
  • NM_001201402.2:c.1736dup
  • NP_000144.2:p.Tyr605Ter
  • NP_001188330.1:p.Tyr582Ter
  • NP_001188331.1:p.Tyr579Ter
  • NC_000014.8:g.88407758_88407759insT
  • NC_000014.8:g.88407759dup
  • NM_000153.3:c.1814dup
  • NM_000153.3:c.1814dupA
Protein change:
Y579*
Links:
dbSNP: rs766007316
NCBI 1000 Genomes Browser:
rs766007316
Molecular consequence:
  • NM_000153.4:c.1814dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001201401.2:c.1745dup - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001201402.2:c.1736dup - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Galactosylceramide beta-galactosidase deficiency (KRB)
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
SCV000919386Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Oct 31, 2017)
germlineclinical testing

Citation Link,

SCV001382219Invitaecriteria provided, single submitter
Pathogenic
(Sep 1, 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

Early progression of Krabbe disease in patients with symptom onset between 0 and 5 months.

Beltran-Quintero ML, Bascou NA, Poe MD, Wenger DA, Saavedra-Matiz CA, Nichols MJ, Escolar ML.

Orphanet J Rare Dis. 2019 Feb 18;14(1):46. doi: 10.1186/s13023-019-1018-4.

PubMed [citation]
PMID:
30777126
PMCID:
PMC6378723

The Twitcher mouse: an enzymatically authentic model of human globoid cell leukodystrophy (Krabbe disease).

Kobayashi T, Yamanaka T, Jacobs JM, Teixeira F, Suzuki K.

Brain Res. 1980 Dec 8;202(2):479-83.

PubMed [citation]
PMID:
7437911
See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919386.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Variant summary: The GALC c.1814dupA (p.Tyr605X) variant results in a premature termination codon, predicted to cause a truncated or absent GALC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 2/244526 control chromosomes (gnomAD) at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALC variant (0.0022361). The variant of interest has not, to our knowledge, been reported in affected individuals via publications. An internal patient with Krabbe disease diagnosed as an infant (<1 yo) carried this variant homozygously. A clinical diagnostic laboratory cites the variant with a classification of "pathogenic." Taken together, this variant is classified as likely pathogenic.

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

From Invitae, SCV001382219.2

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

Description

This sequence change creates a premature translational stop signal (p.Tyr605*) in the GALC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs766007316, ExAC 0.01%). This variant has been observed in an individual affected with Krabbe disease (PMID: 30777126). This variant is also known as c.1766dupA in the literature. ClinVar contains an entry for this variant (Variation ID: 633226). Loss-of-function variants in GALC are known to be pathogenic (PMID: 7437911, 9272171, 16607461). 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: Nov 27, 2021

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