NM_000155.4(GALT):c.253-2A>G AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Clinical significance:Pathogenic (Last evaluated: Sep 30, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000022073.15

Allele description [Variation Report for NM_000155.4(GALT):c.253-2A>G]

NM_000155.4(GALT):c.253-2A>G

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.253-2A>G
HGVS:
  • NC_000009.12:g.34647490A>G
  • NG_009029.2:g.5902A>G
  • NG_028966.1:g.306A>G
  • NM_000155.4:c.253-2A>GMANE SELECT
  • NM_001258332.2:c.50+232A>G
  • NC_000009.11:g.34647487A>G
  • NM_000155.2:c.253-2A>G
  • NM_000155.3:c.253-2A>G
Links:
Genetic Testing Registry (GTR): GTR000500512; dbSNP: rs111033661
NCBI 1000 Genomes Browser:
rs111033661
Molecular consequence:
  • NM_001258332.2:c.50+232A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000155.4:c.253-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000631390Invitaecriteria provided, single submitter
Pathogenic
(Sep 30, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000695685Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jun 13, 2016)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV001193839Myriad Women's Health, Inc.criteria provided, single submitter
Pathogenic
(Dec 4, 2019)
unknownclinical testing

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

Citation Link

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

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933

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
See all PubMed Citations (11)

Details of each submission

From Invitae, SCV000631390.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change affects an acceptor splice site in intron 2 of the GALT gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs111033661, ExAC 0.03%). This variant has been observed to co-occur with a second GALT variant in multiple Hispanic individuals affected with galactosemia (PMID: 11754113, 19375122, Invitae). ClinVar contains an entry for this variant (Variation ID: 25142). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GALT are known to be pathogenic (PMID: 22944367). For these reasons, this variant has been classified as Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695685.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

Variant summary: The GALT c.253-2A>G variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a loss of canonical splicing acceptor site and ESEfinder predicts changes to binding motifs for splicing enhancers. This variant was found in 3/121410 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALT variant (0.0028868). This variant has been reported in multiple affected individuals in both homozygous and compound heterozygous status. One homozygous patient had an erythrocyte GALT activity of one-third of the normal value (Velazquez-Aragon_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

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

From Myriad Women's Health, Inc., SCV001193839.2

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

Description

NM_000155.3(GALT):c.253-2A>G(aka IVS2-2A>G) is classified as pathogenic in the context of galactosemia. Sources cited for classification include the following: PMID 22944367, 18956253, 19375122 and 11754113. Classification of NM_000155.3(GALT):c.253-2A>G(aka IVS2-2A>G) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

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

Last Updated: Nov 27, 2021

Support Center