Submissions for variant NM_000155.4(GALT):c.691C>T (p.Arg231Cys) (rs111033749)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185919	SCV000238872	pathogenic	not provided	2016-11-29	criteria provided, single submitter	clinical testing	The R231C missense mutation in the GALT gene has been reported previously in association with galactosemia (Boutron et al., 2012). The variant is found in GALT panel(s).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000185919	SCV000340775	pathogenic	not provided	2018-02-15	criteria provided, single submitter	clinical testing
Counsyl	RCV000022184	SCV000486527	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2016-06-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022184	SCV000695700	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2016-11-14	criteria provided, single submitter	clinical testing	Variant summary: The GALT c.691C>T (p.Arg231Cys) variant involves the alteration of a conserved nucleotide and is located in the intersubunit interface of the protein (Boutron_2012). 4/4 in silico tools predict a damaging outcome for this variant. This variant has been reported multiple patients with galactosemia in homozygous or compound heterozygous state with other pathogenic variants (Alfadhel_2016, Boutron_2012, Schadewaldt_2003) and is absent in 121210 control chromosomes. A functional study showed this variant leads to loss of enzymatic activity (Coelho_2014). Another missense change (p.R231H) at this residue has also been reported in association with galactosemia (ARUP, ClinVar). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae	RCV000022184	SCV000820402	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2019-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 231 of the GALT protein (p.Arg231Cys). The arginine residue is highly 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 observed in individuals with low GALT enzyme activity, findings that are highly specific for galactose-1-phosphate uridylyltransferase deficiency (PMID: 14518827, 22944367, Invitae). ClinVar contains an entry for this variant (Variation ID: 25246). Experimental studies have shown that this missense change results in a GALT protein with reduced enzyme activity (PMID: 25814382, 25614870). A different missense substitution at this codon (p.Arg231His) has been determined to be pathogenic (PMID: 22944367, 25614870, 7550229, 11152465). This suggests that the arginine residue is critical for GALT protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories	RCV000022184	SCV000042866	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2012-12-04	no assertion criteria provided	clinical testing	Converted during submission to Pathogenic.