ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.864C>T (p.Asn288=) (rs372134800)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508394 SCV000603798 uncertain significance not specified 2017-02-14 criteria provided, single submitter clinical testing
Invitae RCV000545786 SCV000631396 uncertain significance Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2018-10-09 criteria provided, single submitter clinical testing This sequence change affects codon 288 of the GALT mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GALT protein. This variant is present in population databases (rs372134800, ExAC 0.05%). This variant has been reported in the literature in combination with another rare GALT variant in an individual affected with galactosemia (PMID: 22944367). This variant has been observed in an individual with absent GALT activity, findings that are highly specific for galactosemia (PMID: 22944367). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant has uncertain impact on GALT function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000545786 SCV000791583 uncertain significance Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2017-05-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000508394 SCV000919398 uncertain significance not specified 2018-12-03 criteria provided, single submitter clinical testing Variant summary: GALT c.864C>T alters a non-conserved nucleotide resulting in a synonymous change. The variant allele was found at a frequency of 4e-05 in 277414 control chromosomes (gnomAD). Computational tools predict a significant impact on normal splicing: One predict the variant strengthens a cryptic 3 acceptor site. The variant allele was found at a frequency of 4e-05 in 277414 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in GALT causing Galactosemia (4e-05 vs 0.0029), allowing no conclusion about variant significance. c.864C>T has been reported in the literature in compound heterozygous individuals affected with Galactosemia (McDonald 2009, Boutron 2012). One of these reports also noted that the diagnosis was confirmed by absent GALT activity in erythrocytes in all their cases, though no patient specific data were provided (Boutron 2012). The variant has also been reported in homozygosity in a sample from an individual that had only a residual GALT activity; and although no information was provided on the patient's phenotype, the measured enzyme activity was specific for galactosemia (Yuzyuk 2018). A conference abstract (McDonald 2009) described that cDNA containing the variant of interest (from a proband and father) was void of exon 9, although they both had additional variants leading to a complex haplotype (N288N, T292T and H315H) and it is not clear if the exon skipping effect was caused solely by our variant of interest or a combination effect due to this specific haplotype. These data indicate that the variant may be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of these laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Mendelics RCV000545786 SCV001137807 benign Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2019-05-28 criteria provided, single submitter clinical testing

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