NM_000155.4(GALT):c.329-2A>C AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Clinical significance:Pathogenic (Last evaluated: Mar 28, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000022085.8

Allele description [Variation Report for NM_000155.4(GALT):c.329-2A>C]

NM_000155.4(GALT):c.329-2A>C

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.329-2A>C
HGVS:
  • NC_000009.12:g.34647655A>C
  • NG_009029.2:g.6067A>C
  • NG_028966.1:g.471A>C
  • NM_000155.4:c.329-2A>CMANE SELECT
  • NM_001258332.2:c.51-177A>C
  • NC_000009.11:g.34647652A>C
  • NM_000155.2:c.329-2A>C
  • NM_000155.3:c.329-2A>C
Links:
dbSNP: rs111033667
NCBI 1000 Genomes Browser:
rs111033667
Molecular consequence:
  • NM_001258332.2:c.51-177A>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000155.4:c.329-2A>C - 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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000485293Counsylcriteria provided, single submitter
Pathogenic
(Jan 21, 2016)
unknownclinical testing

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

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

SCV000917425Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Dec 24, 2018)
germlineclinical testing

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

Citation Link,

SCV000953624Invitaecriteria provided, single submitter
Pathogenic
(Mar 28, 2020)
germlineclinical testing

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

SCV001163233Baylor Geneticscriteria provided, single submitter
Pathogenicgermlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene.

Tyfield L, Reichardt J, Fridovich-Keil J, Croke DT, Elsas LJ 2nd, Strobl W, Kozak L, Coskun T, Novelli G, Okano Y, Zekanowski C, Shin Y, Boleda MD.

Hum Mutat. 1999;13(6):417-30. Review.

PubMed [citation]
PMID:
10408771

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
See all PubMed Citations (8)

Details of each submission

From Counsyl, SCV000485293.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917425.1

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

Description

Variant summary: GALT c.329-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3' acceptor site. These predictions are supported by the evidence that patient with homozygous allele has no measurable GALT activity (Zekanowsko_1999). The variant allele was found at a frequency of 2e-05 in 246254 control chromosomes. c.329-2A>C has been reported in the literature in multiple individuals affected with Galactosemia (Elsas_1995, Zekanowski_1999, Zekanowski_2001, Boutron_2012, Bosch_2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in unmeasurable activity (Zekanowski_1999). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

From Invitae, SCV000953624.3

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

Description

This sequence change affects an acceptor splice site in intron 3 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 (rs111033667, ExAC 0.01%). Disruption of this splice site have been observed in individuals affected with galactosemia (PMID: 7887416, 10399107). This variant is also known as IVS3nt-2A>C in the literature. ClinVar contains an entry for this variant (Variation ID: 25154). 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 Baylor Genetics, SCV001163233.1

#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 20, 2021

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