NM_000155.4(GALT):c.1030C>A (p.Gln344Lys) AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Clinical significance:Pathogenic (Last evaluated: Sep 23, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000022266.17

Allele description [Variation Report for NM_000155.4(GALT):c.1030C>A (p.Gln344Lys)]

NM_000155.4(GALT):c.1030C>A (p.Gln344Lys)

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.1030C>A (p.Gln344Lys)
HGVS:
  • NC_000009.12:g.34649535C>A
  • NG_009029.2:g.7947C>A
  • NG_028966.1:g.2351C>A
  • NM_000155.4:c.1030C>AMANE SELECT
  • NM_001258332.1:c.703C>A
  • NM_001258332.2:c.703C>A
  • NP_000146.2:p.Gln344Lys
  • NP_001245261.1:p.Gln235Lys
  • NP_001245261.1:p.Gln235Lys
  • NC_000009.11:g.34649532C>A
  • NM_000155.1:c.1030C>A
  • NM_000155.2:c.1030C>A
  • NM_000155.3:c.1030C>A
  • P07902:p.Gln344Lys
Protein change:
Q235K
Links:
UniProtKB: P07902#VAR_002630; dbSNP: rs111033814
NCBI 1000 Genomes Browser:
rs111033814
Molecular consequence:
  • NM_000155.4:c.1030C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258332.1:c.703C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258332.2:c.703C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase (GALAC1)
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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000052460Women's Health and Genetics/Laboratory Corporation of America, LabCorpno assertion criteria providedPathogenic
(Jun 12, 2015)
germlineclinical testing

SCV000793554Counsylno assertion criteria providedLikely pathogenic
(Jun 26, 2019)
unknownclinical testing

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

SCV000835443Invitaecriteria provided, single submitter
Pathogenic
(Sep 23, 2020)
germlineclinical testing

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

SCV000885501ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Jul 6, 2018)
germlineclinical testing

Citation Link,

SCV001163254Baylor Geneticscriteria provided, single submitter
Pathogenicgermlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Molecular basis of classic galactosemia from the structure of human galactose 1-phosphate uridylyltransferase.

McCorvie TJ, Kopec J, Pey AL, Fitzpatrick F, Patel D, Chalk R, Shrestha L, Yue WW.

Hum Mol Genet. 2016 Jun 1;25(11):2234-2244. Epub 2016 Mar 22.

PubMed [citation]
PMID:
27005423
PMCID:
PMC5081055

The rate of de novo galactose synthesis in patients with galactose-1-phosphate uridyltransferase deficiency.

Berry GT, Moate PJ, Reynolds RA, Yager CT, Ning C, Boston RC, Segal S.

Mol Genet Metab. 2004 Jan;81(1):22-30.

PubMed [citation]
PMID:
14728988
See all PubMed Citations (9)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052460.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Counsyl, SCV000793554.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000835443.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces glutamine with lysine at codon 344 of the GALT protein (p.Gln344Lys). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another GALT variant in individuals affected with galactosemia (PMID: 11397328, 11754113, Invitae). ClinVar contains an entry for this variant (Variation ID: 25320). This variant has been reported to affect GALT protein function (PMID: 23319291). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885501.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The GALT c.1030C>A; p.Gln344Lys variant (rs111033814) has been reported in patients diagnosed with hereditary galactosemia (Elsas 1998, Berry 2000, Yang 2001). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 25320) and observed on only 2 alleles in the Genome Aggregation Database. The highly conserved glutamine at codon 344 is located at the subunit interface and is predicted to be important for maintaining inter-subunit hydrogen bonds and stabilize the enzyme complex (Facchiano 2010). Functional characterization indicates that, when found in trans with another pathogenic GALT variant, the p.Gln344Lys variant abrogates GALT activity in erythrocytes (Berry 2000). Based on available information, this variant is considered pathogenic. References: Berry G et al. Galactose breath testing distinguishes variant and severe galactose-1-phosphate uridyltransferase genotypes. Pediatr Res. 2000; 48(3):323-8. Elsas LJ et al. The molecular biology of galactosemia. Genet Med. 1998; 1(1):40-8. Facchiano A et al. Analysis of galactosemia-linked mutations of GALT enzyme using a computational biology approach. Protein Eng Des Sel. 2010; 23(2):103-13. Yang Y et al. Molecular analysis in newborns from Texas affected with galactosemia. Hum Mutat. 2002; 19(1):82-3.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV001163254.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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