NM_000153.4(GALC):c.387C>G (p.Tyr129Ter) AND Galactosylceramide beta-galactosidase deficiency

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 30, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000672034.4

Allele description [Variation Report for NM_000153.4(GALC):c.387C>G (p.Tyr129Ter)]

NM_000153.4(GALC):c.387C>G (p.Tyr129Ter)

Gene:

GALC:galactosylceramidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q31.3

Genomic location:

Preferred name:

NM_000153.4(GALC):c.387C>G (p.Tyr129Ter)

HGVS:

NC_000014.9:g.87986544G>C
NG_011853.3:g.12020C>G
NM_000153.4:c.387C>GMANE SELECT
NM_001201401.2:c.318C>G
NM_001201402.2:c.309C>G
NP_000144.2:p.Tyr129Ter
NP_001188330.1:p.Tyr106Ter
NP_001188331.1:p.Tyr103Ter
NC_000014.8:g.88452888G>C
NG_011853.2:g.12020C>G
NM_000153.3:c.387C>G

Protein change:

Y103*

Links:

dbSNP: rs1240965365

NCBI 1000 Genomes Browser:

rs1240965365

Molecular consequence:

NM_000153.4:c.387C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001201401.2:c.318C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001201402.2:c.309C>G - nonsense - [Sequence Ontology: SO:0001587]

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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Homo sapiens keratin associated protein 22-1, mRNA (cDNA clone MGC:126731 IMAGE:8069188), complete cds
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000797089	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Jan 11, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003442360	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 30, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 27638593, 30777126, 7437911, 9272171, 16607461, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000797089

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Jan 11, 2018)

unknown

clinical testing

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

Citation Link,

SCV003442360

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 30, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Expression of individual mutations and haplotypes in the galactocerebrosidase gene identified by the newborn screening program in New York State and in confirmed cases of Krabbe's disease.

Saavedra-Matiz CA, Luzi P, Nichols M, Orsini JJ, Caggana M, Wenger DA.

J Neurosci Res. 2016 Nov;94(11):1076-83. doi: 10.1002/jnr.23905.

PubMed [citation]

PMID:: 27638593

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

See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000797089.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003442360.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects GALC function (PMID: 27638593). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 556087). This variant is also known as p.Y113*. This premature translational stop signal has been observed in individual(s) with Krabbe disease (PMID: 30777126). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr129*) in the GALC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALC are known to be pathogenic (PMID: 7437911, 9272171, 16607461).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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