ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.329-2A>C (rs111033667)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000022085 SCV000485293 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2016-01-21 criteria provided, single submitter clinical testing
GeneDx RCV000505778 SCV000238866 pathogenic not provided 2018-12-19 criteria provided, single submitter clinical testing The c.329-2A>C variant in the GALT gene has been reported previously, using alternate nomenclature bp 956 A>C (IVSC), in association with galactosemia, in affected individuals who were heterozygous for the c.329-2A>C variant and another variant. (Elsas et al., 1995; Boutron et al., 2012). This splice site variant destroys the canonical splice donor site in intron 3. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.329-2A>C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.329-2A>C as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000022085 SCV000917425 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2018-12-24 criteria provided, single submitter clinical testing 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.
Invitae RCV000022085 SCV000953624 likely pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2018-11-26 criteria provided, single submitter clinical testing 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%). This variant has been observed in trans (on the opposite chromosome) with two GALT variants (in cis) in an individual affected with galactosemia (PMID:  7887416). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Research and Development, ARUP Laboratories RCV000022085 SCV000042761 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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