ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.563A>G (p.Gln188Arg) (rs75391579)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000185917 SCV000603785 pathogenic not provided 2017-08-01 criteria provided, single submitter clinical testing The GALT c.563A>G, p.Gln188Arg variant is a common pathogenic variant in the GALT gene, and has been reported in multiple patients with galactosemia (Reichardt 1991, Viggiano 2015). Functional characterization of the variant protein indicates a significantly reduced enzymatic activity compared to wildtype (Coelho 2014, Elsas 1994, Elsevier 1996, Lai 1999, Reichardt 1991, Riehman 2001), and increased thermal instability (Coelho 2014, Elsevier 1996). References: Coelho A et al. Functional and structural impact of the most prevalent missense mutations in classic galactosemia. Mol Genet Genomic Med. 2014; 2(6):484-96. Elsas LJ et al. A common mutation associated with the Duarte galactosemia allele. Am J Hum Genet. 1994; 54(6):1030-6. Elsevier J et al. The Q188R mutation in human galactose-1-phosphate uridylyltransferase acts as a partial dominant negative. J Biol Chem. 1996; 271(50):32002-7. Lai K et al. The biochemical role of glutamine 188 in human galactose-1-phosphate uridyltransferase. J Biol Chem. 1999; 274(10):6559-66. 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; 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; 276(14):10634-40. 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; 559(2):112-8.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000185917 SCV000281612 pathogenic not provided 2014-10-24 criteria provided, single submitter clinical testing
Counsyl RCV000003798 SCV000485147 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2015-11-24 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000185917 SCV000700771 pathogenic not provided 2018-03-26 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000003798 SCV000611197 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000185917 SCV000238870 pathogenic not provided 2018-12-05 criteria provided, single submitter clinical testing The Q188R variant is the most common variant in classic galactosemic patients of Caucasianethnicity, occurring on approximately 70% of mutant alleles and is associated with a severe clinicalphenotype and undetectable GALT levels in homozygous individuals (Elsas and Lai, 1998; Bosch et al.,2005).
GeneReviews RCV000003798 SCV000147995 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2014-04-03 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000003798 SCV000052468 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Invitae RCV000003798 SCV000631394 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 188 of the GALT protein (p.Gln188Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs75391579, ExAC 0.2%). This rare missense change is a prevalent GALT mutation which has been reported as homozygous or co-occurring with a second GALT variant in multiple individuals and families affected with galactosemia (PMID: 1897530, 25592817, 7887417, 21188552, Invitae). This variant is also known as Q188R in the literature. ClinVar contains an entry for this variant (Variation ID: 3614). Experimental studies have shown that this variant impacts the function of the GALT protein and dramatically reduces enzymatic activity (PMID: 25614870, 11152465, 9772178, 7887417). For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000003798 SCV000538030 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2016-01-27 criteria provided, single submitter clinical testing The c.563A>G (p.Gln188Arg) missense variant in the GALT gene has been previously reported in multiple affected individuals, often in trans with other pathogenic variants (Q188P, R33W, N314D) in the GALT gene (Reichardt et al., 1991; Elsas et al., 1995a; Elsas et al., 1995b; Tran et al., 2015). In addition, the prevalence of this variant is significantly higher in affected individuals relative to unaffected individuals (OR = 99.45; 95% CI = 6.11-1617.36) and accounts for 70% of Galactosemia cases (Elsas et al., 1993; Elsas et al., 1995a; Elsas et al., 1995b; Tyfield et al., 1999). Multiple functional studies have demonstrated this variant causes reduced enzymatic activity of galactose-1-phosphate uridyltransferase (Reichardt et al., 1991; Elsas et al., 1994; Lai et al., 1999). This c.563A>G is reported at low frequency in the control population databases (Exome Sequencing Project [ESP] = 0.267%, 1000 Genomes = 0.2%, and ExAC = 0.205%). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP = 4.77; CADD = 21.1; PolyPhen = 1; SIFT = 0). GALT is the only gene in which pathogenic variants are known to cause Galactosemia. Multiple reputable diagnostic laboratories have reported this variant as pathogenic in individuals affected with Galactosemia. Therefore, this collective evidence supports the classification of the c.563A>G (p.Gln188Arg) as a recessive Pathogenic variant for Galactosemia.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825563 SCV000966889 pathogenic Galactosemia 2018-07-18 criteria provided, single submitter clinical testing The p.Gln188Arg variant in GALT is the most common cause of Galactosemia, accoun ting for at least 50% of alleles in Caucasian and other populations and has been reported homozygously or in trans with other pathogenic alleles in more than 10 0 individuals with Galactosemia (Reichardt 1991, Elsas 1994, Gort 2006, Tyfield 1999, Velazquez-Aragon 2008, Ozgul 2013, Viggiano 2015). This variant has also b een reported in ClinVar (Variation ID: 3614). This variant has been identified i n 0.265% (336/126700) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs75391579). Although this var iant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Many established functional assay s have demonstrated reduced protein function of less than 1% due to the p.Gln188 Arg allele (Reichardt 1991, Elsas 1995, Geeganage 1998, Tyfield 1999, Lai 1999, Riehman 2001, Coelho 2014, McCorvie 2016). Additionally, computational predictio n tools and conservation analyses suggest that this variant may impact the prote in, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for Gala ctosemia in an autosomal recessive manner. ACMG/AMP criteria applied: PM3_VerySt rong, PS3_Moderate, PP3
OMIM RCV000003798 SCV000023963 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 1996-12-13 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000003798 SCV000042830 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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