ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.253-2A>G (rs111033661)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000185912 SCV000228800 pathogenic not provided 2015-10-23 criteria provided, single submitter clinical testing
GeneDx RCV000185912 SCV000238865 pathogenic not provided 2017-04-26 criteria provided, single submitter clinical testing The c.253-2A>G splice site mutation in the GALT gene has been previously reported in Hispanic individuals with galactosemia (Yang et al., 2002). This mutation destroys the canonical splice acceptor site in intron 2, and is expected to cause abnormal gene splicing. We interpret c.253-2 A>G to be a pathogenic mutation.The variant is found in GALT panel(s).
Invitae RCV000022073 SCV000631390 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2020-09-30 criteria provided, single submitter clinical testing 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000022073 SCV000695685 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2016-06-13 criteria provided, single submitter clinical testing 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.
Myriad Women's Health, Inc. RCV000022073 SCV001193839 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2019-12-04 criteria provided, single submitter clinical testing 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.
Research and Development, ARUP Laboratories RCV000022073 SCV000042749 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.

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