VCV000025178.21 - ClinVar

NM_000155.4(GALT):c.443G>A (p.Arg148Gln)

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.

(10)

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_000155.4(GALT):c.443G>A (p.Arg148Gln)

Variation ID: 25178 Accession: VCV000025178.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9p13.3 9: 34647897 (GRCh38) [ NCBI UCSC ] 9: 34647894 (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	Apr 4, 2013	Nov 24, 2024	Feb 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000155.4:c.443G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000146.2:p.Arg148Gln	missense
NM_001258332.2:c.116G>A	NP_001245261.1:p.Arg39Gln	missense
NC_000009.12:g.34647897G>A
NC_000009.11:g.34647894G>A
NG_009029.2:g.6309G>A
NG_028966.1:g.713G>A
	P07902:p.Arg148Gln

... more HGVS ... less HGVS

Protein change

R39Q

Other names

Canonical SPDI

NC_000009.12:34647896:G:A

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.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA259394 UniProtKB: P07902#VAR_002578 dbSNP: rs111033694 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.
GALT		-	-	GRCh38 GRCh37	723	888

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.
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Feb 20, 2024	RCV000022114.19
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 8, 2023	RCV000723398.8
Galactosemia	Pathogenic (1)	no assertion criteria provided	Mar 17, 2017	RCV001826492.2

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.
Pathogenic (Oct 21, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001822996.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Comment: Expression studies found that the R148Q variant was associated with GALT enzyme activity below the limits of detection (Coelho et al., 2014); Not observed at … (more) Expression studies found that the R148Q variant was associated with GALT enzyme activity below the limits of detection (Coelho et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 31980526, 7887416, 25614870, 25525159, 20008339) (less)
Pathogenic (Jan 10, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000631392.6 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (7) PubMed: 7887416‚ 15841485‚ 19375122‚ 22944367‚ 25614870‚ 1373122‚ 25268296 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 148 of the GALT protein (p.Arg148Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 148 of the GALT protein (p.Arg148Gln). This variant is present in population databases (rs111033694, gnomAD 0.01%). This missense change has been observed in individuals with galactosemia (PMID: 7887416, 15841485, 19375122, 22944367). ClinVar contains an entry for this variant (Variation ID: 25178). 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 GALT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALT function (PMID: 25614870). This variant disrupts the p.Arg148 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1373122, 7887416, 15841485, 22944367, 25268296). 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)
Pathogenic (Feb 20, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001163238.2 First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024
Pathogenic (May 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002769257.2 First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024	Publications: PubMed (4) PubMed: 17041746‚ 17957157‚ 22944367‚ 25614870 Comment: A heterozygous missense variant was identified, NM_000155.3(GALT):c.443G>A in exon 5 of 11 of the GALT gene. This substitution is predicted to create a minor amino … (more) A heterozygous missense variant was identified, NM_000155.3(GALT):c.443G>A in exon 5 of 11 of the GALT gene. This substitution is predicted to create a minor amino acid change from arginine to glutamine at position 148 of the protein, NP_000146.2(GALT):p.(Arg148Gln). The arginine at this position has moderate conservation (100 vertebrates, UCSC), and is located within the GalP_UDP_transf functional domain. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0024% (6 heterozygotes, 0 homozygotes). The variant has been previously reported pathogenic in multiple patients with galactosemia (ClinVar, Boutron, A. et al. (2012), Gort, L. et al. (2006)). In addition, functional studies show that this variant results in null enzyme activity (Coelho, A. I. et al. (2014)). Different variants in the same codon resulting in changes to tryptophan, glycine and proline have also been shown to cause galactosemia (ClinVar, Barbouth, D. S. et al. (2007)). Analysis of parental samples indicated this variant was maternally inherited. Based on information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
Likely pathogenic (Feb 10, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000789695.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (6) PubMed: 11397328‚ 15841485‚ 22944367‚ 19375122‚ 25614870‚ 23749220
Pathogenic (May 27, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000230859.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 7887416 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GALT Number of individuals with the variant: 2 Sex: mixed
Pathogenic (Feb 12, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000917420.1 First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019	Publications: PubMed (7) PubMed: 10408771‚ 15841485‚ 17041746‚ 19375122‚ 7671959‚ 7887416‚ 22944367 Comment: Variant summary: GALT c.443G>A (p.Arg148Gln) results in a conservative amino acid change located in the N-terminal of the Galactose-1-phosphate uridyl transferase, of the encoded protein … (more) Variant summary: GALT c.443G>A (p.Arg148Gln) results in a conservative amino acid change located in the N-terminal of the Galactose-1-phosphate uridyl transferase, of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 246264 control chromosomes in gnomAD. This frequency is not significantly higher than expected for a pathogenic variant in GALT causing Galactosemia (2.8e-05 vs 2.90E-03), allowing no conclusion about variant significance. The variant, c.443G>A, has been reported in the literature in multiple individuals affected with Galactosemia (Elsas_1995, Bosch_2005, Gort_2009, Boutron_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Dec 20, 2021)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV004814136.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The GALT c.443G>A p(.Arg148Gln) missense variant has been identified in individuals with a phenotype consistent with galactosemia, including at least one in a homozygous state … (more) The GALT c.443G>A p(.Arg148Gln) missense variant has been identified in individuals with a phenotype consistent with galactosemia, including at least one in a homozygous state and one in a compound heterozygous state (Elsas et al. 1995; Bosch et al. 2005; Gort et al. 2006; Boutron et al. 2012). The highest frequency of this allele in the Genome Aggregation Database is 0.000145 in the Latino/Admixed American population (version 2.1.1). The c.443G>A variant lies within the galactose-1-phosphate uridyl transferase, N-terminal domain, in which multiple missense variants have been previously reported as likely pathogenic or pathogenic for galactosemia. Computational modeling predicts damaging effect of the variant on GALT function, and in vitro studies showed that the p.Arg148Gln change results in undetectable enzyme activity (Facchiano and Marabotti 2010; Coelho et al. 2014). Additionally, an alternative amino acid change at the same position, the p.Arg148Trp, has been reported in individuals affected with galactosemia (Elsas et al. 1995; Bosch et al. 2005; Boutron et al. 2012). Based on the available evidence, the c.443G>A p.(Arg148Gln) variant is classified as pathogenic for galactosemia. (less)
Pathogenic (Sep 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005413875.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (14) PubMed: 10408771‚ 11397328‚ 15841485‚ 17041746‚ 20008339‚ 22944367‚ 23749220‚ 25614870‚ 31589614‚ 31845337‚ 31980526‚ 32954279‚ 34440436‚ 7887416 Comment: PP4, PM2_moderate, PM3, PM5, PS3 Number of individuals with the variant: 1
Pathogenic (Mar 17, 2017)	no assertion criteria provided Method: clinical testing	Galactosemia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002085208.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022

Comment:

Expression studies found that the R148Q variant was associated with GALT enzyme activity below the limits of detection (Coelho et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 31980526, 7887416, 25614870, 25525159, 20008339)

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 148 of the GALT protein (p.Arg148Gln). This variant is present in population databases (rs111033694, gnomAD 0.01%). This missense change has been observed in individuals with galactosemia (PMID: 7887416, 15841485, 19375122, 22944367). ClinVar contains an entry for this variant (Variation ID: 25178). 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 GALT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALT function (PMID: 25614870). This variant disrupts the p.Arg148 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1373122, 7887416, 15841485, 22944367, 25268296). 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:

A heterozygous missense variant was identified, NM_000155.3(GALT):c.443G>A in exon 5 of 11 of the GALT gene. This substitution is predicted to create a minor amino acid change from arginine to glutamine at position 148 of the protein, NP_000146.2(GALT):p.(Arg148Gln). The arginine at this position has moderate conservation (100 vertebrates, UCSC), and is located within the GalP_UDP_transf functional domain. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0024% (6 heterozygotes, 0 homozygotes). The variant has been previously reported pathogenic in multiple patients with galactosemia (ClinVar, Boutron, A. et al. (2012), Gort, L. et al. (2006)). In addition, functional studies show that this variant results in null enzyme activity (Coelho, A. I. et al. (2014)). Different variants in the same codon resulting in changes to tryptophan, glycine and proline have also been shown to cause galactosemia (ClinVar, Barbouth, D. S. et al. (2007)). Analysis of parental samples indicated this variant was maternally inherited. Based on information available at the time of curation, this variant has been classified as PATHOGENIC.

Comment:

Variant summary: GALT c.443G>A (p.Arg148Gln) results in a conservative amino acid change located in the N-terminal of the Galactose-1-phosphate uridyl transferase, of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 246264 control chromosomes in gnomAD. This frequency is not significantly higher than expected for a pathogenic variant in GALT causing Galactosemia (2.8e-05 vs 2.90E-03), allowing no conclusion about variant significance. The variant, c.443G>A, has been reported in the literature in multiple individuals affected with Galactosemia (Elsas_1995, Bosch_2005, Gort_2009, Boutron_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The GALT c.443G>A p(.Arg148Gln) missense variant has been identified in individuals with a phenotype consistent with galactosemia, including at least one in a homozygous state and one in a compound heterozygous state (Elsas et al. 1995; Bosch et al. 2005; Gort et al. 2006; Boutron et al. 2012). The highest frequency of this allele in the Genome Aggregation Database is 0.000145 in the Latino/Admixed American population (version 2.1.1). The c.443G>A variant lies within the galactose-1-phosphate uridyl transferase, N-terminal domain, in which multiple missense variants have been previously reported as likely pathogenic or pathogenic for galactosemia. Computational modeling predicts damaging effect of the variant on GALT function, and in vitro studies showed that the p.Arg148Gln change results in undetectable enzyme activity (Facchiano and Marabotti 2010; Coelho et al. 2014). Additionally, an alternative amino acid change at the same position, the p.Arg148Trp, has been reported in individuals affected with galactosemia (Elsas et al. 1995; Bosch et al. 2005; Boutron et al. 2012). Based on the available evidence, the c.443G>A p.(Arg148Gln) variant is classified as pathogenic for galactosemia.

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
Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center.	Barbosa-Gouveia S	Genes	2021	PMID: 34440436
Deep phenotyping classical galactosemia: clinical outcomes and biochemical markers.	Welsink-Karssies MM	Brain communications	2020	PMID: 32954279
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
The 1-(13) C galactose breath test in GALT deficient patients distinguishes NBS detected variant patients but does not predict outcome in classical phenotypes.	Welsink-Karssies MM	Journal of inherited metabolic disease	2020	PMID: 31845337
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
Functional and structural impact of the most prevalent missense mutations in classic galactosemia.	Coelho AI	Molecular genetics & genomic medicine	2014	PMID: 25614870
Endogenous galactose formation in galactose-1-phosphate uridyltransferase deficiency.	Schadewaldt P	Archives of physiology and biochemistry	2014	PMID: 25268296
A frequent splicing mutation and novel missense mutations color the updated mutational spectrum of classic galactosemia in Portugal.	Coelho AI	Journal of inherited metabolic disease	2014	PMID: 23749220
Mutation spectrum in the French cohort of galactosemic patients and structural simulation of 27 novel missense variations.	Boutron A	Molecular genetics and metabolism	2012	PMID: 22944367
Analysis of galactosemia-linked mutations of GALT enzyme using a computational biology approach.	Facchiano A	Protein engineering, design & selection : PEDS	2010	PMID: 20008339
An update on the molecular analysis of classical galactosaemia patients diagnosed in Spain and Portugal: 7 new mutations in 17 new families.	Gort L	Medicina clinica	2009	PMID: 19375122
Screening newborns for galactosemia using total body galactose oxidation to CO2 in expired air.	Barbouth DS	Pediatric research	2007	PMID: 17957157
Mutational spectrum of classical galactosaemia in Spain and Portugal.	Gort L	Journal of inherited metabolic disease	2006	PMID: 17041746
Identification of novel mutations in classical galactosemia.	Bosch AM	Human mutation	2005	PMID: 15841485
Outcomes analysis of verbal dyspraxia in classic galactosemia.	Robertson A	Genetics in medicine : official journal of the American College of Medical Genetics	2000	PMID: 11397328
Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene.	Tyfield L	Human mutation	1999	PMID: 10408771
Galactosemia: a strategy to identify new biochemical phenotypes and molecular genotypes.	Elsas LJ	American journal of human genetics	1995	PMID: 7887416
A molecular approach to galactosemia.	Elsas LJ 2nd	European journal of pediatrics	1995	PMID: 7671959
Characterization of two missense mutations in human galactose-1-phosphate uridyltransferase: different molecular mechanisms for galactosemia.	Reichardt JK	Genomics	1992	PMID: 1373122
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GALT	-	-	-	-
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Text-mined citations for rs111033694 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000155.4(GALT):c.443G>A (p.Arg148Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs111033694 ...