NM_000153.4(GALC):c.328+6A>G AND Galactosylceramide beta-galactosidase deficiency

Clinical significance:Uncertain significance (Last evaluated: Aug 19, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000330221.4

Allele description [Variation Report for NM_000153.4(GALC):c.328+6A>G]

NM_000153.4(GALC):c.328+6A>G

Gene:
GALC:galactosylceramidase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q31.3
Genomic location:
Preferred name:
NM_000153.4(GALC):c.328+6A>G
HGVS:
  • NC_000014.9:g.87988138T>C
  • NG_011853.2:g.10426A>G
  • NM_000153.4:c.328+6A>GMANE SELECT
  • NM_001201401.1:c.259+6A>G
  • NM_001201402.1:c.250+6A>G
  • NC_000014.8:g.88454482T>C
  • NM_000153.3:c.328+6A>G
Links:
dbSNP: rs201977747
NCBI 1000 Genomes Browser:
rs201977747
Molecular consequence:
  • NM_000153.4:c.328+6A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001201401.1:c.259+6A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001201402.1:c.250+6A>G - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000389263Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Jan 12, 2018)
germlineclinical testing

Citation Link,

SCV001411970Invitaecriteria provided, single submitter
Uncertain significance
(Aug 19, 2019)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001466006Natera, Inc.no assertion criteria providedUncertain significance
(Apr 18, 2020)
germlineclinical testing

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

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV000389263.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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

From Invitae, SCV001411970.1

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

Description

This sequence change falls in intron 3 of the GALC gene. It does not directly change the encoded amino acid sequence of the GALC protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs201977747, ExAC 0.02%). This variant has not been reported in the literature in individuals with GALC-related disease. ClinVar contains an entry for this variant (Variation ID: 314757). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From Natera, Inc., SCV001466006.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 6, 2021

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