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

Total submissions: 7

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	2019-07-15	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.
Integrated Genetics/Laboratory Corporation of America	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.
GeneReviews	RCV000022073	SCV000147992	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2014-04-03	no assertion criteria provided	literature only