Submissions for variant NM_000155.4(GALT):c.626A>G (p.Tyr209Cys) (rs111033744)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Integrated Genetics/Laboratory Corporation of America	RCV000022167	SCV000052471	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000185918	SCV000110069	pathogenic	not provided	2016-05-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000185918	SCV000238871	pathogenic	not provided	2018-04-13	criteria provided, single submitter	clinical testing	The Y209C variant is a common pathogenic variant in the Caucasian population and has been reported in several unrelated individuals with galactosemia (Elsas et al., 1998; Zekanowski et al., 1999; Malone et al., 2011; Sartippour et al., 2014). Functional analysis of Y209C found that it is associated with significantly reduced, but not absent GALT activity (Liu et al., 2012). The Y209C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The Y209C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, we interpret Y209C to be a pathogenic variant.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	RCV000185918	SCV000281374	pathogenic	not provided	2015-09-14	criteria provided, single submitter	clinical testing
Invitae	RCV000022167	SCV000952487	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2018-09-28	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine with cysteine at codon 209 of the GALT protein (p.Tyr209Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs111033744, ExAC 0.006%). This variant has been observed in several individuals affected with galactosemia (PMID: 11397328, 16540753, 10399107). ClinVar contains an entry for this variant (Variation ID: 25231). Experimental studies have shown that this missense change reduces GALT enzymatic activity (PMID: 22743281). This variant disrupts the p.Tyr209 amino acid residue in GALT. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 10399107), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories	RCV000022167	SCV000042849	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2012-12-04	no assertion criteria provided	clinical testing	Converted during submission to Pathogenic.
GeneReviews	RCV000022167	SCV000147998	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2014-04-03	no assertion criteria provided	literature only
Counsyl	RCV000022167	SCV000677910	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2015-10-15	no assertion criteria provided	clinical testing