Submissions for variant NM_000155.4(GALT):c.997C>T (p.Arg333Trp)

dbSNP: rs111033800

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000003794	SCV000052480	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Eurofins Ntd Llc (ga)	RCV000723400	SCV000110084	pathogenic	not provided	2016-09-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000003794	SCV000220483	likely pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2014-07-08	criteria provided, single submitter	literature only
Fulgent Genetics, Fulgent Genetics	RCV000003794	SCV000611198	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2021-08-24	criteria provided, single submitter	clinical testing
Invitae	RCV000003794	SCV000631399	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 333 of the GALT protein (p.Arg333Trp). This variant is present in population databases (rs111033800, gnomAD 0.003%). This missense change has been observed in individual(s) with classic or Duarte variant galactosemia (PMID: 1897530, 10384398, 10399107, 18207281, 25592817). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3610). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALT protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GALT function (PMID: 1897530, 11152465, 12208137). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000003794	SCV001158634	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2018-07-31	criteria provided, single submitter	clinical testing	The GALT c.997C>T; p.Arg333Trp variant (rs111033800) has been described in the compound heterozygous state in multiple individuals and families affected with classic or Duarte galactosemia (Ashino 1995, Carney 2009, Feillet 2008, Hirokawa 1999, Hughes 2009, Knerr 2013, Reichardt 1991, Viggiano 2015, Zaffanello 2005, Zekanowski 1999). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 3610), and is found in the general population with an overall allele frequency of 0.002% (5/246258 alleles) in the Genome Aggregation Database. In vitro functional studies of the variant protein demonstrates impaired GALT enzyme function (Reichardt 1991, Riehman 2001). Additionally, other variants at this codon (p.Arg333Gln, p.Arg333Gly, p.Arg333Leu) have been reported in individuals with galactosemia and are considered pathogenic (Leslie 1992, Ng 2003, Singh 2012, Tyfield 1999). Based on available information, the p.Arg333Trp variant is considered pathogenic. REFERENCES Ashino J et al. Molecular characterization of galactosemia (type 1) mutations in Japanese. Hum Mutat. 1995;6(1):36-43. Carney AE et al. Origins, distribution and expression of the Duarte-2 (D2) allele of galactose-1-phosphate uridylyltransferase. Hum Mol Genet. 2009 May 1;18(9):1624-32. Feillet F et al. Evidence of cataplerosis in a patient with neonatal classical galactosemia presenting as citrin deficiency. J Hepatol. 2008 Mar;48(3):517-22. Hirokawa H et al. Molecular basis for phenotypic heterogeneity in galactosaemia: prediction of clinical phenotype from genotype in Japanese patients. Eur J Hum Genet. 1999 Oct-Nov;7(7):757-64. Hughes J et al. Outcomes of siblings with classical galactosemia. J Pediatr. 2009 May;154(5):721-6. Knerr I et al. Leptin levels in children and adults with classic galactosaemia. JIMD Rep. 2013;9:125-131. Leslie N et al. The human galactose-1-phosphate uridyltransferase gene. Genomics. 1992 Oct;14(2):474-80. Ng W et al. Two adult galactosaemia females with normal ovarian function and identical GALT mutations (Q188R/R333G). J Inherit Metab Dis. 2003;26(1):75-9. Reichardt J et al. Molecular characterization of two galactosemia mutations: correlation of mutations with highly conserved domains in galactose-1-phosphate uridyl transferase. Am J Hum Genet. 1991 Oct;49(4):860-7. Riehman K et al. Relationship between genotype, activity, and galactose sensitivity in yeast expressing patient alleles of human galactose-1-phosphate uridylyltransferase. J Biol Chem. 2001 Apr 6;276(14):10634-40. Singh R et al. Biochemical and molecular characterization of GALT gene from Indian galactosemia patients: identification of 10 novel mutations and their structural and functional implications. Clin Chim Acta. 2012 Dec 24;414:191-6. Tyfield L et al. Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. Hum Mutat. 1999;13(6):417-30. Viggiano E et al. Clinical and molecular spectra in galactosemic patients from neonatal screening in northeastern Italy: structural and functional characterization of new variations in the galactose-1-phosphate uridyltransferase (GALT) gene. Gene. 2015 Apr 1;559(2):112-8. Zaffanello M et al. Neonatal screening, clinical features and genetic testing for galactosemia. Genet Med. 2005 Mar;7(3):211-2. Zekanowski C et al. Molecular characterization of Polish patients with classical galactosaemia. J Inherit Metab Dis. 1999 Jun;22(5):679-82.
GeneDx	RCV000723400	SCV001874162	pathogenic	not provided	2021-08-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate very low galactose-1-phosphate uridyl transferase activity compared to wild-type (Riehman et al., 2001; Reichardt et al. 1991); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 31589614, 31194252, 25124065, 25174965, 26419375, 15633893, 22944367, 10408771, 11678552, 25622686, 20663501, 21960482, 8598637, 18813948, 8522334, 15775761, 20547145, 7474913, 10384398, 9686364, 8051928, 12208137, 23430559, 19181333, 18207281, 8692963, 17143577, 10573007, 8943248, 8892021, 19224951, 10399107, 7550229, 2011574, 1897530, 20008339, 11152465, 25592817, 25087612)
Mayo Clinic Laboratories, Mayo Clinic	RCV000723400	SCV002525794	pathogenic	not provided	2021-04-28	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM2, PP4
Baylor Genetics	RCV000003794	SCV004198531	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-07-05	criteria provided, single submitter	clinical testing
OMIM	RCV000003794	SCV000023959	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	1996-12-13	no assertion criteria provided	literature only
Lifecell International Pvt. Ltd	RCV000003794	SCV001478354	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826410	SCV002085252	pathogenic	Galactosemia	2017-03-17	no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000003794	SCV003927874	pathogenic	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase	2023-04-01	no assertion criteria provided	clinical testing