NM_000153.4(GALC):c.1158_1161+6del AND Galactosylceramide beta-galactosidase deficiency

Clinical significance:Pathogenic (Last evaluated: Mar 2, 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:
RCV001044546.2

Allele description [Variation Report for NM_000153.4(GALC):c.1158_1161+6del]

NM_000153.4(GALC):c.1158_1161+6del

Gene:
GALC:galactosylceramidase [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
14q31.3
Genomic location:
Preferred name:
NM_000153.4(GALC):c.1158_1161+6del
HGVS:
  • NC_000014.9:g.87963382_87963391del
  • NG_011853.2:g.35177_35186del
  • NG_011853.3:g.35177_35186del
  • NM_000153.4:c.1158_1161+6delMANE SELECT
  • NM_001201401.2:c.1089_1092+6del
  • NM_001201402.2:c.1080_1083+6del
  • NC_000014.8:g.88429726_88429735del
  • NM_000153.3:c.1158_1161+6del
  • NM_000153.3:c.1158_1161+6del10
Links:
dbSNP: rs759068540
NCBI 1000 Genomes Browser:
rs759068540
Molecular consequence:
  • NM_000153.4:c.1158_1161+6del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001201401.2:c.1089_1092+6del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001201402.2:c.1080_1083+6del - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV001208350Invitaecriteria provided, single submitter
Pathogenic
(Dec 13, 2019)
germlineclinical testing

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

SCV001339011Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Mar 2, 2020)
germlineclinical testing

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

Citation Link

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Early infantile Krabbe disease: results of the World-Wide Krabbe Registry.

Duffner PK, Barczykowski A, Jalal K, Yan L, Kay DM, Carter RL.

Pediatr Neurol. 2011 Sep;45(3):141-8. doi: 10.1016/j.pediatrneurol.2011.05.007.

PubMed [citation]
PMID:
21824559
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001208350.1

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

Description

This variant results in the deletion of part of exon 10 (c.1158_1161+6del) of the GALC gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individual(s) with Krabbe disease (PMID: 21824559). This variant is also known as c.1110_1113+6del in the literature. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001339011.1

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

Description

Variant summary: GALC c.1158_1161+6del10 is located in the end of exon 10 including a canonical splice-site at intron 10 and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. 4/4 computational tools predict a significant impact on normal splicing and predict the variant abolishes a canonical 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 248926 control chromosomes (gnomAD). c.1158_1161+6del10 has been reported in the literature in individuals affected with Krabbe Disease (Duffner_2011, Beltran-Quintero_2019). These data indicate that the variant may be associated with disease. At least one in vitro study reports this variant effect results in decreasing normal GALC activity. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Oct 24, 2021

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