Submissions for variant NM_000155.4(GALT):c.199C>T (p.Arg67Cys) (rs111033658)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000723719	SCV000110053	pathogenic	not provided	2013-07-30	criteria provided, single submitter	clinical testing
Invitae	RCV000022067	SCV000631389	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2018-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 67 of the GALT protein (p.Arg67Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the homozygous and compound heterozygous state in individuals affected with galactosemia (PMID: 8598637, 22944367). ClinVar contains an entry for this variant (Variation ID: 25137). Experimental studies have shown that this missense change reduces the GALT enzymatic activity in vitro and is not able to functionally rescue yeasts cells null for GALT (PMID: 11152465). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022067	SCV000917422	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2018-05-07	criteria provided, single submitter	clinical testing	Variant summary: GALT c.199C>T (p.Arg67Cys) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal (IPR005849) domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 30924 control chromosomes (gnomAD). c.199C>T has been reported in the literature in individuals affected with Galactosemia (Sommer 1995, Boutron 2012). These data indicate that the variant may be associated with disease. Two publications reported experimental evidence evaluating an impact on protein function (Sommer 1995, Riehman 2001). The most pronounced variant effect resulted in <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Research and Development, ARUP Laboratories	RCV000022067	SCV000042742	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2012-12-04	no assertion criteria provided	clinical testing	Converted during submission to Pathogenic.