ClinVar Miner

Submissions for variant NM_000155.4(GALT):c.512T>C (p.Phe171Ser) (rs111033715)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000723392 SCV000885500 pathogenic not provided 2018-05-30 criteria provided, single submitter clinical testing The GALT c.512T>C; p.Phe171Ser variant (rs111033715) is described in several studies to have reduced or a complete loss of enzymatic activity (Crews 2000, McCorvie 2013, Reichardt 1992, Riehman 2001, Wang 1998). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 3616). It is found in the general African American population with a low allele frequency of 0.02% (5/24016 alleles) in the Genome Aggregation Database. The phenylalanine at codon 171 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Crews C et al. Functional consequence of substitutions at residue 171 in human galactose-1-phosphate uridylyltransferase. J Biol Chem. 2000 Jul 28;275(30):22847-53. McCorvie TJ et al. Misfolding of galactose 1-phosphate uridylyltransferase can result in type I galactosemia. Biochim Biophys Acta. 2013 Aug;1832(8):1279-93. Reichardt JK et al. Molecular characterization of two galactosemia mutations and one polymorphism: implications for structure-function analysis of human galactose-1-phosphate uridyltransferase. Biochemistry. 1992 Jun 23;31(24):5430-3. 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. Wang BB et al. Molecular and biochemical basis of galactosemia. Mol Genet Metab. 1998 Apr;63(4):263-9.
Counsyl RCV000003800 SCV000485247 likely pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2016-03-09 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723392 SCV000110063 pathogenic not provided 2018-02-13 criteria provided, single submitter clinical testing
GeneReviews RCV000003800 SCV000147994 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2014-04-03 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000003800 SCV000695694 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2016-09-22 criteria provided, single submitter clinical testing Variant summary: The GALT c.512T>C (p.Phe171Ser) variant is located in the Galactose-1-phosphate uridyl transferase, N-terminal domain causing a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121466, which does not exceed the estimated maximal expected allele frequency for a pathogenic GALT variant of 1/346. Multiple publications cite the variant in affected individuals as homozygous or compound heterozygous, along with multiple clinical diagnostic laboratories citing the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Invitae RCV000003800 SCV000631393 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 2018-03-16 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 171 of the GALT protein (p.Phe171Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is present in population databases (rs111033715, ExAC 0.01%). This variant has been reported as homozygous and in combination with other variants in the GALT gene in individuals affected with galactosemia (PMID: 1610789, 18956253, 27176039, 22944367, 23022339). ClinVar contains an entry for this variant (Variation ID: 3616). Experimental studies have shown that this missense change results in a GALT protein with reduced enzymatic activity (PMID: 10811638 , 1610789, 23583749). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003800 SCV000023965 pathogenic Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase 1992-06-23 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000003800 SCV000042816 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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