NM_000155.4(GALT):c.396C>A (p.His132Gln) AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 24, 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:: RCV000022103.14

Allele description [Variation Report for NM_000155.4(GALT):c.396C>A (p.His132Gln)]

NM_000155.4(GALT):c.396C>A (p.His132Gln)

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.396C>A (p.His132Gln)

HGVS:

NC_000009.12:g.34647850C>A
NG_009029.2:g.6262C>A
NG_028966.1:g.666C>A
NM_000155.4:c.396C>AMANE SELECT
NM_001258332.2:c.69C>A
NP_000146.2:p.His132Gln
NP_001245261.1:p.His23Gln
NC_000009.11:g.34647847C>A
NM_000155.3:c.396C>A
P07902:p.His132Gln

Protein change:

H23Q

Links:

UniProtKB: P07902#VAR_068537; dbSNP: rs367543256

NCBI 1000 Genomes Browser:

rs367543256

Molecular consequence:

NM_000155.4:c.396C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258332.2:c.69C>A - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001230380	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 24, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22944367, 28649529, 22461411, 28492532
SCV002547871	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 2, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19224951, 22461411, 22944367, 27308838, 28649529 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001230380

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 24, 2023)

germline

clinical testing

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

SCV002547871

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(May 2, 2022)

germline

clinical testing

PubMed (5)
[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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Origins, distribution and expression of the Duarte-2 (D2) allele of galactose-1-phosphate uridylyltransferase.

Carney AE, Sanders RD, Garza KR, McGaha LA, Bean LJ, Coffee BW, Thomas JW, Cutler DJ, Kurtkaya NL, Fridovich-Keil JL.

Hum Mol Genet. 2009 May 1;18(9):1624-32. doi: 10.1093/hmg/ddp080. Epub 2009 Feb 18.

PubMed [citation]

PMID:: 19224951
PMCID:: PMC2667289

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001230380.5

#	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 histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 132 of the GALT protein (p.His132Gln). This variant is present in population databases (rs367543256, gnomAD 0.004%). This missense change has been observed in individual(s) with galactosemia (PMID: 22461411, 22944367, 28649529; Invitae). ClinVar contains an entry for this variant (Variation ID: 25170). 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. Experimental studies have shown that this missense change affects GALT function (PMID: 22461411). 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002547871.1

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

Description

Variant summary: GALT c.396C>A (p.His132Gln) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, 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 allele was found at a frequency of 4e-06 in 251696 control chromosomes (gnomAD and publication data). c.396C>A has been reported in the literature in compound heterozygous individuals affected with Galactosemia (Carney_2009, Tang_2012, Boutron_2012, Cocanougher_2015). These data indicate that the variant is likely to be associated with disease. At least one functional study showed this variant disrupts the active site of the enzyme and results in in active enzyme (Tang_2012). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and 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

Last Updated: Feb 20, 2024

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