ClinVar Miner

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

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Total submissions: 8
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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

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