VCV000915993.15 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 915993 Accession: VCV000915993.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q31.3 14: 87976437 (GRCh38) [ NCBI UCSC ] 14: 88442781 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 4, 2020	Feb 14, 2024	Jan 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000153.4:c.673G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000144.2:p.Ala225Thr	missense
NM_001201401.2:c.604G>A	NP_001188330.1:p.Ala202Thr	missense
NM_001201402.2:c.595G>A	NP_001188331.1:p.Ala199Thr	missense
NC_000014.9:g.87976437C>T
NC_000014.8:g.88442781C>T
NG_011853.3:g.22127G>A

... more HGVS ... less HGVS

Protein change

A199T, A202T, A225T

Other names

Canonical SPDI

NC_000014.9:87976436:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

dbSNP: rs1436074042 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GALC		-	-	GRCh38 GRCh37	1332	1445

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Galactosylceramide beta-galactosidase deficiency	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 1, 2024	RCV001195147.11
Spastic ataxia	Pathogenic (1)	criteria provided, single submitter	Jul 12, 2021	RCV001644930.1
not provided	Likely pathogenic (1)	criteria provided, single submitter	Nov 3, 2019	RCV001508371.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Apr 16, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Galactosylceramide beta-galactosidase deficiency Affected status: yes Allele origin: inherited	Department of Molecular and Human Genetics, Baylor College of Medicine Accession: SCV001334106.1 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Publications: PubMed (1) PubMed: 32576985 Comment on evidence: in trans with GALC exons 11-17 deletion
Likely pathogenic (Nov 03, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001714489.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Publications: PubMed (2) PubMed: 26795590‚ 27638593 Comment: PS3, PM2, PM5 Number of individuals with the variant: 1
Pathogenic (Jul 12, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Spastic ataxia Affected status: yes Allele origin: unknown	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris Accession: SCV001519291.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021
Pathogenic (Jan 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Galactosylceramide beta-galactosidase deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001517585.4 First in ClinVar: Mar 14, 2021 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 26795590‚ 27638593‚ 30777126 Comment: 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). … (more) 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. (less)
Likely pathogenic (Feb 13, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Galactosylceramide beta-galactosidase deficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003844599.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Publications: PubMed (3) PubMed: 26795590‚ 27638593‚ 34445196 Comment: 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 … (more) 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. (less)
Uncertain significance (-)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Galactosylceramide beta-galactosidase deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001528220.2 First in ClinVar: Mar 22, 2021 Last updated: Mar 18, 2023
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
NGS in Hereditary Ataxia: When Rare Becomes Frequent.	Galatolo D	International journal of molecular sciences	2021	PMID: 34445196
CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels.	Yuan B	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32576985
Early progression of Krabbe disease in patients with symptom onset between 0 and 5 months.	Beltran-Quintero ML	Orphanet journal of rare diseases	2019	PMID: 30777126
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	Journal of neuroscience research	2016	PMID: 27638593
Newborn screening for Krabbe disease in New York State: the first eight years' experience.	Orsini JJ	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26795590

Text-mined citations for rs1436074042 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1436074042 ...