NM_000155.4(GALT):c.152G>T (p.Arg51Leu) AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Aug 14, 2023
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:: RCV001964239.6

Allele description [Variation Report for NM_000155.4(GALT):c.152G>T (p.Arg51Leu)]

NM_000155.4(GALT):c.152G>T (p.Arg51Leu)

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.152G>T (p.Arg51Leu)

HGVS:

NC_000009.12:g.34647158G>T
NG_009029.2:g.5570G>T
NM_000155.4:c.152G>TMANE SELECT
NM_001258332.2:c.-51G>T
NP_000146.2:p.Arg51Leu
NC_000009.11:g.34647155G>T
NM_000155.3:c.152G>T
P07902:p.Arg51Leu

Links:

UniProtKB: P07902#VAR_002553; dbSNP: rs111033648

NCBI 1000 Genomes Browser:

rs111033648

Molecular consequence:

NM_001258332.2:c.-51G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000155.4:c.152G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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Pediatric ovarian germ cell tumor
Pediatric ovarian germ cell tumor

MedGen
C0796664[conceptid] (1)
MedGen
LOC124410345 [Diprion similis]
LOC124410345 [Diprion similis]
Gene ID:124410345

Gene
ugt1a1 [Poecilia latipinna]
ugt1a1 [Poecilia latipinna]
Gene ID:106959622

Gene
LOC103640441 [Zea mays]
LOC103640441 [Zea mays]
Gene ID:103640441

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002256159	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 14, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15841485, 31954591, 22944367, 29892033, 34030713, 28492532
SCV002765940	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 18, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10408771, 20008339, 22944367, 11678552, 34030713, 29892033 Citation Link,
SCV004198519	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 7, 2023)	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

SCV002256159

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 14, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV002765940

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Nov 18, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV004198519

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 7, 2023)

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

Identification of novel mutations in classical galactosemia.

Bosch AM, Ijlst L, Oostheim W, Mulders J, Bakker HD, Wijburg FA, Wanders RJ, Waterham HR.

Hum Mutat. 2005 May;25(5):502.

PubMed [citation]

PMID:: 15841485

The Galactose Index measured in fibroblasts of GALT deficient patients distinguishes variant patients detected by newborn screening from patients with classical phenotypes.

Welsink-Karssies MM, van Weeghel M, Hollak CEM, Elfrink HL, Janssen MCH, Lai K, Langendonk JG, Oussoren E, Ruiter JPN, Treacy EP, de Vries M, Ferdinandusse S, Bosch AM.

Mol Genet Metab. 2020 Mar;129(3):171-176. doi: 10.1016/j.ymgme.2020.01.002. Epub 2020 Jan 9.

PubMed [citation]

PMID:: 31954591

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002256159.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg51 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15841485, 31954591). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1470556). This missense change has been observed in individual(s) with galactosemia (PMID: 22944367, 29892033, 34030713). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 51 of the GALT protein (p.Arg51Leu).

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002765940.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: GALT c.152G>T (p.Arg51Leu) results in a non-conservative amino acid change located in the N-terminal domain (IPR005849) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251422 control chromosomes (gnomAD). c.152G>T has been reported in the literature in multiple individuals affected with Galactosemia (e.g. Tyfield_1999, Zekanowski_2001, Boutron_2012, Bech_2018, Jezela-Stanek_2021). These data indicate that the variant is very likely to be associated with disease. Molecular modelling has suggested that this variant is likely to impact the structure of the GALT protein (e.g. Facchiano_2010). However, to our knowledge, an effect on protein function has yet to be evaluated with experimental studies. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and the variant as likely pathogenic. Based on the evidence outlined above, the variant was 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, SCV004198519.1

#	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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