NM_000153.4(GALC):c.673G>A (p.Ala225Thr) AND Galactosylceramide beta-galactosidase deficiency

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 1, 2024
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:: RCV001195147.11

Allele description [Variation Report for NM_000153.4(GALC):c.673G>A (p.Ala225Thr)]

NM_000153.4(GALC):c.673G>A (p.Ala225Thr)

Gene:

GALC:galactosylceramidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q31.3

Genomic location:

Preferred name:

NM_000153.4(GALC):c.673G>A (p.Ala225Thr)

HGVS:

NC_000014.9:g.87976437C>T
NG_011853.3:g.22127G>A
NM_000153.4:c.673G>AMANE SELECT
NM_001201401.2:c.604G>A
NM_001201402.2:c.595G>A
NP_000144.2:p.Ala225Thr
NP_001188330.1:p.Ala202Thr
NP_001188331.1:p.Ala199Thr
NC_000014.8:g.88442781C>T
NG_011853.2:g.22127G>A
NM_000153.3:c.673G>A
p.Ala225Thr

Protein change:

A199T

Links:

dbSNP: rs1436074042

NCBI 1000 Genomes Browser:

rs1436074042

Molecular consequence:

NM_000153.4:c.673G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001201401.2:c.604G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001201402.2:c.595G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV001334106	Department of Molecular and Human Genetics, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 16, 2020)	inherited	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 32576985
SCV001517585	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 1, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27638593, 26795590, 30777126, 28492532
SCV003844599	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Feb 13, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26795590, 27638593, 34445196 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001334106

Department of Molecular and Human Genetics, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 16, 2020)

inherited

clinical testing

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

SCV001517585

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 1, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV003844599

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Feb 13, 2023)

germline

clinical testing

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

Citation Link

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	inherited	yes	1	1	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

CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels.

Yuan B, Wang L, Liu P, Shaw C, Dai H, Cooper L, Zhu W, Anderson SA, Meng L, Wang X, Wang Y, Xia F, Xiao R, Braxton A, Peacock S, Schmitt E, Ward PA, Vetrini F, He W, Chiang T, Muzny D, Gibbs RA, et al.

Genet Med. 2020 Oct;22(10):1633-1641. doi: 10.1038/s41436-020-0864-8. Epub 2020 Jun 24.

PubMed [citation]

PMID:: 32576985
PMCID:: PMC8445517

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 (7)

Details of each submission

From Department of Molecular and Human Genetics, Baylor College of Medicine, SCV001334106.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

in trans with GALC exons 11-17 deletion

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001517585.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 225 of the GALC protein (p.Ala225Thr). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of Krabbe disease (PMID: 26795590, 27638593; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 915993). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALC protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALC function (PMID: 26795590). This variant disrupts the p.Ala225 amino acid residue in GALC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26795590, 30777126; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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 Baylor Genetics, SCV001528220.2

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003844599.1

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

Description

Variant summary: GALC c.673G>A (p.Ala225Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249302 control chromosomes (gnomAD). c.673G>A has been reported in the literature in individuals affected with Krabbe Disease and was detected in infants with low GALC activity following newborn screening (e.g. Orsini_2016, Saavedra-Martiz_2016, Machado_2021). These data indicate that the variant may be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to result in decreased GALC activity (Saavedra-Martiz_2016). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic (n=4) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001528220	Baylor Genetics	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Uncertain significance	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

SCV001528220

Baylor Genetics

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Uncertain significance

unknown

clinical testing

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

Last Updated: Sep 29, 2024

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Relating variation to medicine