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

gnomAD frequency: 0.00001  dbSNP: rs111033749

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185919	SCV000238872	pathogenic	not provided	2024-02-26	criteria provided, single submitter	clinical testing	Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 25614870); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27629047, 33636947, 36515074, 25614870, 22944367, 30718057, 25814382, 31980526, 31130284)
Eurofins Ntd Llc (ga)	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022184	SCV000820402	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-11-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 231 of the GALT protein (p.Arg231Cys). This variant is present in population databases (rs111033749, gnomAD 0.01%). This missense change has been observed in individual(s) with low GALT enzyme activity, findings that are highly specific for galactose-1-phosphate uridylyltransferase deficiency (PMID: 14518827, 22944367; internal data). ClinVar contains an entry for this variant (Variation ID: 25246). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GALT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALT function (PMID: 25614870, 25814382). This variant disrupts the p.Arg231 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7550229, 11152465, 22944367, 25614870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000022184	SCV003924296	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-05-08	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000022184	SCV005675419	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-05-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001831602	SCV002085229	pathogenic	Galactosemia	2020-09-23	no assertion criteria provided	clinical testing