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

gnomAD frequency: 0.00001  dbSNP: rs111033667

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000505778	SCV000238866	pathogenic	not provided	2021-05-25	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 7887416, 10399107, 22944367, 25525159)
Counsyl	RCV000022085	SCV000485293	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2016-01-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-10-19	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. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GALT are known to be pathogenic (PMID: 22944367). This variant is present in population databases (rs111033667, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with galactosemia (PMID: 7887416, 10399107). This variant is also known as IVS3nt-2A>C. 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. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000022085	SCV001163233	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000505778	SCV004226584	pathogenic	not provided	2023-04-24	criteria provided, single submitter	clinical testing	PM2, PM3, PS4_moderate, PVS1
Natera, Inc.	RCV001826491	SCV002085196	pathogenic	Galactosemia	2017-08-29	no assertion criteria provided	clinical testing