NM_000155.4(GALT):c.221T>C (p.Leu74Pro) AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Germline classification:: Conflicting classifications of pathogenicity (4 submissions)
Last evaluated:: Dec 23, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000003799.10

Allele description [Variation Report for NM_000155.4(GALT):c.221T>C (p.Leu74Pro)]

NM_000155.4(GALT):c.221T>C (p.Leu74Pro)

Genes:

LOC130001683:ATAC-STARR-seq lymphoblastoid active region 28314 [Gene]
GALT:galactose-1-phosphate uridylyltransferase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9p13.3

Genomic location:

Preferred name:

NM_000155.4(GALT):c.221T>C (p.Leu74Pro)

HGVS:

NC_000009.12:g.34647227T>C
NG_009029.2:g.5639T>C
NG_028966.1:g.43T>C
NM_000155.4:c.221T>CMANE SELECT
NM_001258332.2:c.19T>C
NP_000146.2:p.Leu74Pro
NP_001245261.1:p.Cys7Arg
NC_000009.11:g.34647224T>C
NM_000155.2:c.221T>C
NM_000155.3:c.221T>C
P07902:p.Leu74Pro

Protein change:

C7R; LEU74PRO

Links:

UniProtKB: P07902#VAR_002557; OMIM: 606999.0007; dbSNP: rs111033663

NCBI 1000 Genomes Browser:

rs111033663

Molecular consequence:

NM_000155.4:c.221T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258332.2:c.19T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Synonyms:: GALACTOSE-1-PHOSPHATE URIDYLYLTRANSFERASE DEFICIENCY; Transferase Deficiency Galactosemia; GALACTOSEMIA I; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009258; MedGen: C0268151; Orphanet: 352; Orphanet: 79239; OMIM: 230400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000023964	OMIM	no assertion criteria provided	Pathogenic (Jun 23, 1992)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001437257	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Sep 24, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 1610789, 23583749, 30718057 Citation Link,
SCV003835281	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 10, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005835679	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 23, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7887416, 30718057, 1610789, 23583749, 28492532

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	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Galactosemia: a strategy to identify new biochemical phenotypes and molecular genotypes.

Elsas LJ, Langley S, Steele E, Evinger J, Fridovich-Keil JL, Brown A, Singh R, Fernhoff P, Hjelm LN, Dembure PP.

Am J Hum Genet. 1995 Mar;56(3):630-9.

PubMed [citation]

PMID:: 7887416
PMCID:: PMC1801164

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000023964.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Reichardt et al. (1992) characterized 2 galactosemia I (GALAC1; 230400) mutations, L74P and F171S (606999.0008), and 1 polymorphism, S135L, in the GALT gene. Both mutations resulted in reduced enzymatic activity on expression studies, whereas the polymorphism resulted in near normal activity. Both mutations involved evolutionarily conserved residues, while the polymorphism occurred in a nonconserved domain.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	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, SCV001437257.1

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

Description

Variant summary: GALT c.221T>C (p.Leu74Pro) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251302 control chromosomes. c.221T>C has been reported in the literature in at least one individual affected with Galactosemia (Reichardt_1992). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Reichardt_1992, McCorvie_2013). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. 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

From Baylor Genetics, SCV003835281.2

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV005835679.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 74 of the GALT protein (p.Leu74Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with classic galactosemia (PMID: 1610789, 7887416, 30718057). ClinVar contains an entry for this variant (Variation ID: 3615). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 1610789, 23583749). 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

Last Updated: Apr 13, 2025

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