NM_000153.4(GALC):c.581G>C (p.Gly194Ala) AND Galactosylceramide beta-galactosidase deficiency

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 23, 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:: RCV001248182.7

Allele description [Variation Report for NM_000153.4(GALC):c.581G>C (p.Gly194Ala)]

NM_000153.4(GALC):c.581G>C (p.Gly194Ala)

Gene:

GALC:galactosylceramidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q31.3

Genomic location:

Preferred name:

NM_000153.4(GALC):c.581G>C (p.Gly194Ala)

HGVS:

NC_000014.9:g.87984395C>G
NG_011853.3:g.14169G>C
NM_000153.4:c.581G>CMANE SELECT
NM_001201401.2:c.512G>C
NM_001201402.2:c.503G>C
NP_000144.2:p.Gly194Ala
NP_001188330.1:p.Gly171Ala
NP_001188331.1:p.Gly168Ala
NC_000014.8:g.88450739C>G
NG_011853.2:g.14169G>C
NM_000153.3:c.581G>C

Protein change:

G168A

Links:

dbSNP: rs963756824

NCBI 1000 Genomes Browser:

rs963756824

Molecular consequence:

NM_000153.4:c.581G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001201401.2:c.512G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001201402.2:c.503G>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001421651	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 23, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9338580, 27638593, 28492532
SCV002791596	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 17, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001421651

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 23, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002791596

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 17, 2021)

unknown

clinical testing

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

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

Molecular genetics of Krabbe disease (globoid cell leukodystrophy): diagnostic and clinical implications.

Wenger DA, Rafi MA, Luzi P.

Hum Mutat. 1997;10(4):268-79. Review.

PubMed [citation]

PMID:: 9338580

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

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001421651.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 194 of the GALC protein (p.Gly194Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Krabbe syndrome (PMID: 9338580). This variant is also known as G178A. ClinVar contains an entry for this variant (Variation ID: 972207). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects GALC function (PMID: 27638593). 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.

#	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

From Fulgent Genetics, Fulgent Genetics, SCV002791596.1

#	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

Last Updated: Sep 29, 2024

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