NM_000155.4(GALT):c.617A>G (p.Gln206Arg) AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 23, 2022
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:: RCV000805776.17

Allele description [Variation Report for NM_000155.4(GALT):c.617A>G (p.Gln206Arg)]

NM_000155.4(GALT):c.617A>G (p.Gln206Arg)

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.617A>G (p.Gln206Arg)

HGVS:

NC_000009.12:g.34648386A>G
NG_009029.2:g.6798A>G
NG_028966.1:g.1202A>G
NM_000155.4:c.617A>GMANE SELECT
NM_001258332.2:c.290A>G
NP_000146.2:p.Gln206Arg
NP_001245261.1:p.Gln97Arg
NC_000009.11:g.34648383A>G
NM_000155.3:c.617A>G

Protein change:

Q206R

Links:

dbSNP: rs1587239309

NCBI 1000 Genomes Browser:

rs1587239309

Molecular consequence:

NM_000155.4:c.617A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258332.2:c.290A>G - 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
SCV000945744	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 23, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22743281, 28492532
SCV001157990	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Likely pathogenic (Nov 6, 2018)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000945744

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 23, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001157990

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Likely pathogenic
(Nov 6, 2018)

germline

clinical testing

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

N- and O-linked glycosylation of total plasma glycoproteins in galactosemia.

Liu Y, Xia B, Gleason TJ, Castañeda U, He M, Berry GT, Fridovich-Keil JL.

Mol Genet Metab. 2012 Aug;106(4):442-54. doi: 10.1016/j.ymgme.2012.05.025. Epub 2012 Jun 12.

PubMed [citation]

PMID:: 22743281
PMCID:: PMC3426456

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

Details of each submission

From Invitae, SCV000945744.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. 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: 650599). This missense change has been observed in individual(s) with galactosemia (PMID: 22743281; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 206 of the GALT protein (p.Gln206Arg).

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001157990.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The GALT c.617A>G; p.Gln206Arg variant is reported in the literature in the homozygous state in an individual with classic galactosemia (Liu 2012). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glutamine at codon 206 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Consistent with these predictions, an in vitro GALT assay suggested the p.Gln206Arg variant exhibits negligible activity compared to wildtype protein (Spencer 2013). Based on available information, this variant is considered to be likely pathogenic. References: Liu Y et al. N- and O-linked glycosylation of total plasma glycoproteins in galactosemia. Mol Genet Metab. 2012 Aug;106(4):442-54. Spencer JB et al. Modifiers of ovarian function in girls and women with classic galactosemia. J Clin Endocrinol Metab. 2013 Jul;98(7):E1257-65.

#	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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