ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.997C>T (p.Arg333Trp) (rs111033800)

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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 RCV000003794 SCV000052480 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 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 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000003794 SCV000631399 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 333 of the GALT protein (p.Arg333Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs111033800, ExAC 0.01%). This variant has been observed as homozygous or in combination with other GALT variants in individuals affected with classic or Duarte variant galactosemia (PMID: 25592817, 10384398, 10399107, 18207281, 1897530). In addition, there is evidence for disease co-segregation in a family (PMID: 19181333). ClinVar contains an entry for this individual (Variation ID: 3610). Experimental studies have shown that this variant impairs GALT enzyme function in vitro (PMID: 11152465, 12208137, 1897530). 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.
OMIM RCV000003794 SCV000023959 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 1996-12-13 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000003794 SCV000042942 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.

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